4,197 Matching Annotations
  1. Aug 2021
    1. As shown in Figure xref A, it was found that high glucose led to a significant increase in the association of plakoglobin with p53, which was blocked by KLK8 knockdown.

      TP53 binds JUP.

    2. Diabetes mellitus increased the association of p53 with both HIF-1α and Smad3 in heart tissues, which was attenuated in KLK8 -/- mice (Figure xref F).

      TP53 binds HIF1A and SMAD3.

    3. In addition, high glucose induced p53 binding to both HIF-1α and Smad3, which was blocked by siRNA targeting KLK8 and plakoglobin (Figure xref A-B).

      TP53 binds HIF1A and SMAD3.

    4. The present study found that upregulation of KLK8 leads to plakoglobin-dependent nuclear translocation of p53, which binds to HIF-1α, and further enhances the transactivation effect of HIF-1α on the TGF-β1 promoter and consequently upregulates TGF-β1 expression at the transcriptional level.

      TP53 binds HIF1A.

    5. Altogether, these data suggest that upregulation of KLK8 leads to plakoglobin-dependent association of p53 with HIF-1α, which further enhances the transactive effect of HIF-1α on the TGF-β1 promoter.

      TP53 binds HIF1A.

    6. KLK8 overexpression induced the association of p53 with HIF-1α, which was blocked by plakoglobin knockdown (Figure xref F).

      TP53 binds HIF1A.

    7. The present study found that upregulation of KLK8 leads to plakoglobin dependent nuclear translocation of p53, which binds to HIF-1alpha, and further enhances the transactivation effect of HIF-1alpha on the TGF-beta1 promoter and consequently upregulates TGF-beta1 expression at the transcriptional level.

      TP53 binds HIF1A.

    8. Using ChIP analysis, it was found that high glucose treatment led to a significant increase in the binding of HIF-1α to the TGF-β1 promoter, which was largely blocked in the presence of KLK8 siRNA, plakoglobin siRNA (Figure xref C) or the p53 inhibitor pifithrin-α (Figure xref D).

      TGFB1 binds HIF1A and KLK8.

    9. Using ChIP analysis, the present study confirmed the binding of HIF-1α to the TGF-β1 promoter, which was significantly enhanced by KLK8 overexpression (Figure xref E).

      TGFB1 binds HIF1A and KLK8.

    10. KLK8 overexpression led to a significant increase in the association of plakoglobin with both p53 and TCF-4 (Figure xref C).

      TCF4 binds TP53 and JUP.

    11. The present study found that plakoglobin was associated with p53 and TCF-4 in HCAECs (Figure xref C).

      TCF4 binds TP53 and JUP.

    12. Notably, although KLK8 overexpression led to a significant increase in the association of plakoglobin with both p53 and TCF-4, KLK8-induced EndMT was reduced only by a p53 inhibitor, but not by the inhibitor of β-catenin/TCF-mediated transcription.

      TCF4 binds TP53 and JUP.

    13. While cadherin bound beta-catenin and plakoglobin are required for cell adhesion, membrane uncomplexed beta-catenin and plakoglobin have a function in transducing the Wnt signal from the cell surface to the nucleus XREF_BIBR, XREF_BIBR, XREF_BIBR.

      Cadherin binds CTNNB1.

    14. In addition, KLK8-induced p53 activation promoted the pro-fibrotic reprogramming by TGF-β1 via the cooperation of p53 with Smads in endothelial cells.

      KLK8 activates TP53.

    15. As shown in Figure 11A , it was found that high glucose led to a significant increase in the association of plakoglobin with p53 , which was blocked by KLK8 knockdown .

      KLK8 activates TP53.

    16. In addition, KLK8 induced p53 activation promoted the pro fibrotic reprogramming by TGF-beta1 via the cooperation of p53 with Smads in endothelial cells.

      KLK8 activates TP53.

    17. As shown in Figure XREF_FIG A, it was found that high glucose led to a significant increase in the association of plakoglobin with p53, which was blocked by KLK8 knockdown.

      KLK8 activates TP53.

    18. Taken together, these data highlight the role of KLK8 induced cooperation of p53 with Smad3 in promoting pro EndMT reprogramming by TGF-beta1 in endothelial cells.

      KLK8 activates TP53.

    19. The present study found that KLK8 overexpression significantly increased the association of p53 with Smad3, which was blocked by plakoglobin knockdown.

      KLK8 activates TP53.

    20. KLK8 overexpression induced the association of p53 with HIF-1alpha, which was blocked by plakoglobin knockdown.

      KLK8 activates TP53.

    21. Of note, since KLK8 promotes proliferation and migration in cardiac fibroblasts, a potential contribution of KLK8 induced fibroblast activation to the development of cardiac fibrosis in the context of diabetes can not be excluded.
    22. Cell proliferation assay and Ki67 immunostaining revealed that KLK8 overexpression markedly enhanced the proliferation of cardiac fibroblasts.
    23. These findings indicate that Sp-1 mediates high glucose induced upregulation of KLK8 in endothelial cells.

      SP1 activates KLK8.

    24. Sp-1 mediates high glucose induced upregulation of KLK8 in endothelial cells.

      SP1 activates KLK8.

    25. We then generated a KLK8 report gene by cloning the promoter of human KLK8 into the pGL3 vector , thereby further confirming that high glucose stimulates KLK8 expression through the Sp-1 site in the KLK8 gene .

      glucose activates KLK8.

    26. It was found that the mRNA and protein expression levels of KLK8 were significantly upregulated in a dose-dependent manner in high glucose-treated HCAECs compared with those of normal glucose-treated HCAECs ( Figure 8A-B ) , suggesting that high glucose stimulated KLK8 expression at the transcriptional level .

      glucose activates KLK8.

    27. A major implication of high glucose induced KLK8 upregulation is that KLK8 targeted therapy would have clinical relevance for patients with diabetic myopathy.

      glucose activates KLK8.

    28. These findings indicate that Sp-1 mediates high glucose induced upregulation of KLK8 in endothelial cells.

      glucose activates KLK8.

    29. Sp-1 mediates high glucose induced upregulation of KLK8 in endothelial cells.

      glucose activates KLK8.

    30. KLK8 siRNA not only led to a significant decrease of KLK8 expression in HCAECs, but also blocked the high glucose induced upregulation of KLK8.

      glucose activates KLK8.

    31. High glucose may promote the plakoglobin dependent cooperation of p53 with HIF-1alpha and Smad3, subsequently increasing the expression of TGF-beta1 and the pro EndMT target genes of the TGF-beta1 and Smad signaling pathway in a KLK8 dependent manner both in vitro and in vivo.

      glucose activates TP53.

    32. Taken together, these in vitro and in vivo results suggest that high glucose may promote plakoglobin dependent cooperation of p53 with HIF-1alpha and Smad3, subsequently increasing the expression of TGF-beta1 and its pro EndMT target genes in a KLK8 dependent manner.

      glucose activates TP53.

    33. High glucose promotes plakoglobin dependent cooperation of p53 with HIF-1alpha and Smad, subsequently increasing the expression of TGF-beta1 and its pro fibrotic target genes in a KLK8 dependent manner.

      glucose activates TP53.

    34. The in vitro and in vivo findings further demonstrated that high glucose may promote plakoglobin dependent cooperation of p53 with HIF-1alpha and Smad3, subsequently increasing the expression of TGF-beta1 and the pro EndMT target genes of the TGF-beta1 and Smad signaling pathway in a KLK8 dependent manner.

      glucose activates TP53.

    35. The in vitro and in vivo findings further demonstrated that high glucose may promote plakoglobin dependent cooperation of p53 with HIF-1alpha and Smad3, subsequently increasing the expression of TGF-beta1 and the pro EndMT target genes of the TGF-beta1 and Smad signaling pathway in a KLK8 dependent manner.

      glucose activates TP53.

    1. Downregulation of PTEN expression or inhibiting its biologic activity improves heart function, promotes cardiomyocytes proliferation, reduces cardiac fibrosis as well as dilation, and inhibits apoptosis following ischemic stress such as myocardial infarction.
    2. Downregulation of PTEN expression or inhibiting its biologic activity improves heart function , promotes cardiomyocytes proliferation , reduces cardiac fibrosis as well as dilation , and inhibits apoptosis following ischemic stress such as myocardial infarction .

      PTEN activates apoptotic process.

    1. Collectively, these data indicate that both CYP2C19 and CYP2C9 are important contributors in CBD metabolism to the active metabolite 7-OH-CBD.
    2. Collectively, these data indicate that both CYP2C19 and CYP2C9 are important contributors in CBD metabolism to the active metabolite 7-OH-CBD.
    3. Collectively, these data indicate that both CYP2C19 and CYP2C9 are important contributors in CBD metabolism to the active metabolite 7-OH-CBD.
    4. Collectively, these data indicate that both CYP2C19 and CYP2C9 are important contributors in CBD metabolism to the active metabolite 7-OH-CBD.
    1. Moreover, GAS5 and Smad4 overexpression inhibited LPS- induced chondrocytes apoptosis, while miR-146a overexpression played an opposite role and attenuated the effects of GAS5 and Smad4 overexpression on cell apoptosis.
  2. Jul 2021
    1. PTEN and PTPs all antagonize the insulin signaling as they directly interact with PI3K and IR [XREF_BIBR], and both consist of a cysteine residue in the active site that is highly susceptible to H 2 O 2 -induced oxidation.

      PTEN inhibits INS.

    2. The C2 domain ( amino acids 186-351 ) can bind phospholipid membrane independent of calcium because it lacks the canonical Ca2 + chelating residues in vitro , which makes PTEN inhibit cell migration [ 31 ] .

      PTEN inhibits cell migration.

    3. For instance, H 2 O 2 can induce PTEN oxidation, which inactivates PTEN phosphatase function by establishing a Cys 124 -Cys 71 disulfide bond [XREF_BIBR].

      PTEN inhibits Phosphatase.

    4. For example, the Parkinson disease protein 7 (PARK7) was found to repress the PTEN phosphatase function by binding to PTEN.

      PARK7 inhibits PTEN.

    5. Recently, it has been found that the impairment of PARK2 can induce the suppression of PTEN by S nitrosylation through increase the level of NO [XREF_BIBR].

      PRKN activates PTEN.

    6. Recently , it has been found that the impairment of PARK2 can induce the suppression of PTEN by S-nitrosylation through increase the level of NO [ 55 ] .

      PRKN activates PTEN.

    7. Besides, Prx II deficient MEFs induced PTEN oxidation and increased PI3K and Akt activation when exposed to insulin, which leads to an increase the insulin sensitivity.

      PRX activates PTEN.

    8. Prx III-deficiency also induces the augmentation in both PTEN oxidation and Trx dimerization.

      PRX activates PTEN.

    9. In addition, p300-CREB-binding protein (CBP) has been shown to acetylate PTEN at Lys 402 in the PDZ-binding motif.

      PTEN is acetylated on K402.

    1. It has been demonstrated that Prx I can preserve and promote the tumor-suppressive function of PTEN by preventing oxidation of PTEN under benign oxidative stress via direct interaction.

      PRX activates PTEN.

    2. Also, Prx II deficient cells increased PTEN oxidation and insulin sensitivity.

      PRX activates PTEN.

    1. To examine whether FoxO3a is required for PTEN mediated negative regulation of autophagy, we analyzed the mRNA levels of ATG5, ATG7, and ATG12 in the ipsilateral hippocampus post-ICH.

      PTEN inhibits autophagy.

    2. In the present study, PTEN inhibition not only reduced the levels of autophagy related proteins but also activated the PI3K and AKT pathway in the ipsilateral hippocampus after ICH.

      PTEN inhibits PI3K.

    3. Functionally, our findings confirmed that inhibition of PTEN by PTEN siRNA or specific inhibitor not only ameliorated secondary hippocampal injury but also promoted hippocampal-dependent cognition and memory recovery, suggesting important neuroprotective effects against hemorrhagic insults.
    4. Specifically, PTEN antagonized the PI3K and AKT signaling and downstream effector FoxO3a phosphorylation and subsequently enhanced nuclear translocation of FoxO3a to drive proautophagy gene program, but these changes were diminished upon PTEN inhibition.

      PTEN leads to the dephosphorylation of FOXO3.

    5. Mechanistically, blockage of PTEN could enhance FoxO3a phosphorylation modification to restrict its nuclear translocation and ATG transcription via activating the PI3K and AKT pathway, leading to the suppression of the autophagic program.

      PTEN leads to the dephosphorylation of FOXO3.

    6. Inhibition of PTEN Ameliorates Secondary Hippocampal Injury and Cognitive Deficits after Intracerebral Hemorrhage : Involvement of AKT / FoxO3a / ATG-Mediated Autophagy .
    7. Inhibition of PTEN Ameliorates Secondary Hippocampal Injury and Cognitive Deficits after Intracerebral Hemorrhage : Involvement of AKT / FoxO3a / ATG-Mediated Autophagy Spontaneous intracerebral hemorrhage ( ICH ) commonly causes secondary hippocampal damage and delayed cognitive impairments , but the mechanisms remain elusive .
    8. According to these data, we speculate that posthemorrhagic PTEN elevation triggers the nuclear accumulation of FoxO3a and subsequent transcriptional activation of ATGs, resulting in sequential activation of autophagy.

      PTEN activates FOXO3.

    9. Herein, we identified that ICH induced a significant increase in ATG transcriptional levels including ATG5, ATG7, and ATG12, which was strongly associated with PTEN mediated FoxO3a nuclear translocation.

      PTEN activates FOXO3.

    10. PTEN Inhibition Reverses Secondary Hippocampal Injury Post-ICH.
    11. Also, inactivation of the PI3K/AKT/mTOR pathway has been implicated in PTEN induced autophagy initiation [XREF_BIBR, XREF_BIBR].

      PTEN activates autophagy.

    12. However , blockage of PTEN prominently abolished these ATG transcriptions and subsequent autophagy induction .
    1. Also, the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK) were stimulated by S100A8, which had an analogous effect to the lipopolysaccharide (LPS) treatment ( xref C–E).

      S100A8 leads to the phosphorylation of JNK.

    2. S100A8 Induced Pro Inflammatory Cytokine Production Via Phosphorylation of ERK and JNK in BV-2 Cells.

      S100A8 leads to the phosphorylation of JNK.

    3. Also, the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK) were stimulated by S100A8, which had an analogous effect to the lipopolysaccharide (LPS) treatment (XREF_FIG C-E).

      S100A8 leads to the phosphorylation of JNK.

    4. Also, the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK) were stimulated by S100A8, which had an analogous effect to the lipopolysaccharide (LPS) treatment ( xref C–E).

      S100A8 leads to the phosphorylation of ERK.

    5. S100A8 Induced Pro Inflammatory Cytokine Production Via Phosphorylation of ERK and JNK in BV-2 Cells.

      S100A8 leads to the phosphorylation of ERK.

    6. Also, the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK) were stimulated by S100A8, which had an analogous effect to the lipopolysaccharide (LPS) treatment (XREF_FIG C-E).

      S100A8 leads to the phosphorylation of ERK.

    7. The S100A8 knockdown using shRNA revealed that COX-2 and PGE 2 expression was regulated by S100A8, which suggested that the intracellular increase of microglial S100A8 levels upregulated COX-2 expression and PGE2 secretion, contributing to neuronal death under hypoxic conditions.

      S100A8 increases the amount of PTGS2.

    8. Our study showed that hypoxia increased the production of S100A8 in microglia .

      Hypoxia activates S100A8.

    9. FACS analysis showed that the increase of S100A8 levels in microglia by hypoxia promoted neuronal apoptosis , which was confirmed by immunofluorescence .

      Hypoxia activates S100A8.

    10. In agreement with previous reports, the results of this study confirmed that S100A8 significantly increased the production of IL-6, TNF-alpha, and IL-1beta.

      S100A8 activates IL6.

    11. In our study , the increase of IL-1beta expression by S100A8 indicated that S100A8 was involved in the priming signal for NLRP3 inflammasome assembly in microglia ( Figure 2B ) .

      S100A8 activates IL1B.

    12. In agreement with previous reports, the results of this study confirmed that S100A8 significantly increased the production of IL-6, TNF-alpha, and IL-1beta.

      S100A8 activates IL1B.

    13. These results suggested that S100A8, secreted by neuronal cells under hypoxic conditions, combined with TLR4 of microglia cells, activated the NLRP3 inflammasome priming.

      S100A8 activates NLRP3.

    14. These results strongly suggested that S100A8 induced the NLRP3 inflammasome priming via NF-kappaB activation.

      S100A8 activates NLRP3.

    15. The results suggested that S100A8, secreted by neuronal cells under hypoxic conditions, triggered the priming of NLRP3 in microglial cells, through the TLR4 and NF-kappaB signaling.

      S100A8 activates NLRP3.

    16. In addition, the translocation of NF-kB, which played a pivotal role in regulating the expression and activation of NLRP3, was also increased when cells were treated with S100A8.

      S100A8 activates NLRP3.

    17. In agreement with previous reports, the results of this study confirmed that S100A8 significantly increased the production of IL-6, TNF-alpha, and IL-1beta.

      S100A8 activates TNF.

    18. FACS analysis showed that the increase of S100A8 levels in microglia by hypoxia promoted neuronal apoptosis, which was confirmed by immunofluorescence.
    19. However, for the first time, we showed that up-regulation of microglial S100A8 levels increased neuronal apoptosis after hypoxia, in primary multicellular cultures consisting of neurons, astrocytes, and microglia.
    20. Therefore, this study determined whether S100A8 induced neuronal apoptosis during cerebral hypoxia and elucidated its mechanism of action using in vitro systems, including astrocytes and microglial and neuronal cells, under hypoxic conditions.
    21. S100A8 Knockdown on Microglia Attenuated Neuronal Apoptosis by Hypoxia.
    22. To investigate whether S100A8 expression in microglia induced apoptosis of neuronal cells under hypoxic condition, SH-SY5Y cells were co-cultured with BV-2 cells transfected with S100A8 shRNA for 48 h in a 0.4 mum pore transwell system and under hypoxic conditions (XREF_FIG A, B).
    23. These findings indicated that the expression of S100A8, induced in microglia cells under hypoxic conditions, activated COX-2 expression and PGE 2 secretion to induce the apoptosis of neurons.
    1. Knockdown of S100A8 levels by using shRNA revealed that microglial S100A8 expression activated COX-2 expression, leading to neuronal apoptosis under hypoxia.

      S100A8 increases the amount of PTGS2.

    2. S100A8, secreted from neurons under hypoxia, activated the secretion of tumor necrosis factor (TNF-alpha) and interleukin-6 (IL-6) through phosphorylation of extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) in microglia.

      S100A8 activates IL6.

    3. S100A8, secreted from neurons under hypoxia, activated the secretion of tumor necrosis factor (TNF-alpha) and interleukin-6 (IL-6) through phosphorylation of extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) in microglia.

      S100A8 activates TNF.

    4. The aim of this study was to determine whether S100A8 induced neuronal apoptosis during cerebral hypoxia and elucidate its mechanism of action.
    1. The precise mechanism of how LASP1 promotes PTEN ubiquitination still remains elusive xref .

      LASP1 leads to the ubiquitination of PTEN.

    2. The precise mechanism of how LASP1 promotes PTEN ubiquitination still remains elusive 53.

      LASP1 leads to the ubiquitination of PTEN.

    3. In another study, the heat shock-like protein Clusterin was shown to increase AKT2 activity and promote the motility of both normal and malignant prostate cells via an inhibitory activity on PTEN-S380 phosphorylation and consequent inactivation of PTEN xref .

      PTEN is phosphorylated on S380.

    4. Another study demonstrated that phosphorylation of PTEN on tyrosine 240 by FGFR2 promotes chromatin binding through an interaction with Ki-67, which facilitates the recruitment of RAD51 to promote DNA repair xref . xref summarises these novel functions and signalling axes of nuclear PTEN.

      FGFR2 phosphorylates PTEN on Y240.

    5. One study showed that Nuclear Receptor Binding SET Domain Protein 2 (NSD2)-mediated dimethylation of PTEN promotes 53BP1 interactions and subsequent recruitment to sites of DNA-damage sites 75.

      NSD2 methylates PTEN.

    6. Newer studies add to this small body of data , including an intriguing study where a novel PTEN / ARID4B / PI3K pathway in which PTEN inhibits the expression of ARID4B was characterised .

      PTEN inhibits ARID4B.

    7. PTEN inhibits ARID4B expression and thus prevents the transcriptional activation of ARID4B transcriptional targets PIK3CA and PIK3R2 ( PI3K subunits ) 79 .

      PTEN inhibits ARID4B.

    8. By using specific mutants of PTEN lacking lipid phosphatase function, an early study concluded that PTEN may block cell migration through a protein phosphatase mediated function on focal adhesion kinase (FAK) protein 14.

      PTEN inhibits cell migration.

    9. PTEN and PDHK1 were observed to have a synthetic-lethal relationship, as loss of PTEN and upregulation of PDHK1 in cells induced glycolysis and a dependency on PDHK1 100.
    10. This PTEN/ARID4B/PI3K signalling axis identifies a novel player in the PTEN mediated suppression of the PI3K pathway and provides a new opportunity to design novel therapeutics to target this axis to promote the tumour suppressive functions of PTEN.

      PTEN inhibits PI3K.

    11. In one of these studies, Baker et al. reported that Notch1 can mediate transcriptional suppression of PTEN, resulting in the derepression of PI3K signalling and development of trastuzumab resistance 91.

      NOTCH1 inhibits PTEN.

    12. This study was the first to link the Ras-MAPK and PI3K pathways through Notch1 transcriptional suppression of PTEN 91.

      NOTCH1 inhibits PTEN.

    13. It was reported that PTEN could dephosphorylate PGK1, a glycolytic enzyme and protein kinase with a tumorigenic role in glioblastoma xref .

      PTEN dephosphorylates PGK1.

    14. Dephosphorylation of PGK1 by PTEN was found to inhibit its activity, downstream glycolytic functions, and glioblastoma cell proliferation xref , thereby presenting another mechanism in which PTEN functions as a tumour suppressor.

      PTEN dephosphorylates PGK1.

    15. It was reported that PTEN could dephosphorylate PGK1, a glycolytic enzyme and protein kinase with a tumorigenic role in glioblastoma 99.

      PTEN dephosphorylates PGK1.

    16. Dephosphorylation of PGK1 by PTEN was found to inhibit its activity, downstream glycolytic functions, and glioblastoma cell proliferation 99, thereby presenting another mechanism in which PTEN functions as a tumour suppressor.

      PTEN dephosphorylates PGK1.

    17. Newer studies add to this small body of data, including an intriguing study where a novel PTEN/ARID4B/PI3K pathway in which PTEN inhibits the expression of ARID4B was characterised.

      PTEN decreases the amount of ARID4B.

    18. PTEN inhibits ARID4B expression and thus prevents the transcriptional activation of ARID4B transcriptional targets PIK3CA and PIK3R2 (PI3K subunits) 79.

      PTEN decreases the amount of ARID4B.

    19. Furthermore, nuclear PTEN directly interacted with and inhibited RNA polymerase II (RNAPII)-mediated transcription, where it was involved in direct downregulation of critical transcriptional control genes including AFF4 and POL2RA 80.

      RNApo_II binds PTEN.

    20. Colocalisation of PTEN and PTENalpha promoted the function of PINK1, a mitochondrial-target kinase, and subsequently promoted energy production 105.

      PTEN activates PINK1.

    21. It is known that AKT signaling plays a critical role in the regulation of pre-mRNA splicing 77 and PTEN has been shown to modulate G6PD pre-mRNA splicing in an AKT independent manner 78.

      PTEN activates AKT.

    22. Numb inhibits Notch1, leading to the downregulation of RBP-Jkappa 94, which upregulates PTEN and anti-EMT effectors, leading to the downregulation of p-FAK and pro EMT effectors 94.

      NOTCH1 activates PTEN.

    1. Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

      IL23R inhibits ITGAE.

    2. Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

      IL23R inhibits ITGA1.

    3. CD103 binds E-cadherin, which is highly expressed on epithelia, whereas CD69 antagonizes sphingosine 1-phosphate receptor 1 (S1PR1)-mediated egress from tissues.

      CD69 inhibits S1PR1.

    4. Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

      IL17F inhibits ITGAE.

    5. Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

      IL17F inhibits ITGA1.

    6. Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

      CCR6 inhibits ITGAE.

    7. Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

      CCR6 inhibits ITGA1.

    8. Further validating transcriptional data, CXCR3 expression was higher on CD8 + CD103 + CD49a + Trm cells, whereas IL-23R and CCR6 were preferentially expressed by CD8 + CD103 + CD49a - Trm cells (XREF_FIG G).

      ITGAE increases the amount of IL23R.

    9. Further validating transcriptional data, CXCR3 expression was higher on CD8 + CD103 + CD49a + Trm cells, whereas IL-23R and CCR6 were preferentially expressed by CD8 + CD103 + CD49a - Trm cells (XREF_FIG G).

      ITGAE increases the amount of CCR6.

    10. In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

      ITGA1 increases the amount of PRF1.

    11. In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

      ITGA1 increases the amount of PRF1.

    12. In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

      ITGA1 increases the amount of GZMB.

    13. Accordingly, IL-15-dependent expression of perforin and granzyme B was augmented by IL-6, but not other cytokine combinations tested (XREF_SUPPLEMENTARY C-S2E).

      IL6 increases the amount of GZMB.

    14. Rather, their cytotoxic capacity was primed through IL-2 and IL-15-mediated induction of perforin and granzyme B expression.

      IL2 increases the amount of PRF1.

    15. Rather, their cytotoxic capacity was primed through IL-2 and IL-15-mediated induction of perforin and granzyme B expression.

      IL2 increases the amount of GZMB.

    16. In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

      CD8 increases the amount of PRF1.

    17. In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

      CD8 increases the amount of PRF1.

    18. Moreover, IL-15 stimulation potentiated TCR dependent expression of IL-17 and IFN-gamma by epidermal CD8 + CD103 + CD49a - and IFN-gamma by CD8 + CD103 + CD49a + Trm cells, respectively (XREF_FIG D), substantiating effectual gamma chain receptor signaling in both subsets.

      CD8 increases the amount of IL17A.

    19. In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

      CD8 increases the amount of GZMB.

    20. Further validating transcriptional data, CXCR3 expression was higher on CD8 + CD103 + CD49a + Trm cells, whereas IL-23R and CCR6 were preferentially expressed by CD8 + CD103 + CD49a - Trm cells (XREF_FIG G).

      CD8 increases the amount of IL23R.

    21. Further validating transcriptional data, CXCR3 expression was higher on CD8 + CD103 + CD49a + Trm cells, whereas IL-23R and CCR6 were preferentially expressed by CD8 + CD103 + CD49a - Trm cells (XREF_FIG G).

      CD8 increases the amount of CCR6.

    22. Moreover, IL-15 stimulation potentiated TCR dependent expression of IL-17 and IFN-gamma by epidermal CD8 + CD103 + CD49a - and IFN-gamma by CD8 + CD103 + CD49a + Trm cells, respectively (XREF_FIG D), substantiating effectual gamma chain receptor signaling in both subsets.

      CD8 increases the amount of TCR.

    23. In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

      Trm increases the amount of PRF1.

    24. In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

      Trm increases the amount of PRF1.

    25. In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

      Trm increases the amount of GZMB.

    26. CD103 binds E-cadherin, which is highly expressed on epithelia, whereas CD69 antagonizes sphingosine 1-phosphate receptor 1 (S1PR1)-mediated egress from tissues.

      CDH1 binds ITGAE.

    27. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      IV activates ITGAE.

    28. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      IV activates IFNG.

    29. Relative to the epidermal CD8 + CD103 + CD49a - Trm cells, dermal counterparts produced 3.5-fold less IL-17.

      ITGAE activates IL17A.

    30. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      ITGA1 activates ITGAE.

    31. Relative to the epidermal CD8 + CD103 + CD49a - Trm cells, dermal counterparts produced 3.5-fold less IL-17.

      ITGA1 activates IL17A.

    32. Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

      ITGA1 activates IL17A.

    33. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      ITGA1 activates IFNG.

    34. In human skin epithelia, CD8 + CD49a + Trm cells produced interferon-gamma, whereas CD8 + CD49a - Trm cells produced interleukin-17 (IL-17).

      ITGA1 activates IFNG.

    35. Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

      ITGA1 activates IFNG.

    36. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      ITGA1 activates Trm.

    37. IL-2 and IL-15 Induce Cytotoxic Effector Protein Expression in Epidermal CD8 + CD103 + CD49a + Trm Cells.

      IL2 activates Trm.

    38. Conversely, CD8 + CD49a - Trm cells from psoriasis lesions predominantly generated IL-17 responses that promote local inflammation in this skin disease.
    39. This functional dichotomy was evident in the comparison of distinct immune mediated skin diseases, with skin biopsies from vitiligo patients showing a predominance of cytotoxic CD8 + CD103 + CD49a + Trm cells while skin biopsies from psoriasis patients featured the accumulation of the IL-17 producing CD8 + CD103 + CD49a - counterparts.

      IL17A activates CD8.

    40. Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

      IL15 activates ITGAE.

    41. Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

      IL15 activates ITGA1.

    42. Generally, IFN-gamma contributes to immunity toward intracellular infections while IL-17 provides anti-fungal defense and both of these cytokines initiate inflammatory keratinocyte responses.

      IFNG activates immune response.

    43. In line withincreased CD49a frequencies, IFN-gamma producing Trm cells were enriched in vitiligo lesions (XREF_FIG G).

      IFNG activates Trm.

    44. Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

      IL23R activates IL17A.

    45. Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

      IL17F activates IL17A.

    46. Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

      CCR6 activates IL17A.

    47. TCR engagement using anti-CD3 antibodies also preferentially induced IFN-gamma by epidermal CD8 + CD103 + CD49a + Trm cells (XREF_FIG D).

      TCR activates Trm.

    48. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      CD8 activates ITGAE.

    49. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      CD8 activates ITGA1.

    50. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      CD8 activates Trm.

    51. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      Collagen activates ITGAE.

    52. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      Collagen activates IFNG.

    53. TNF and IL-2 were abundantly produced by dermal and epidermal Trm cell subsets (XREF_FIG B and 6C).

      carbon atom activates IL2.

    54. TNF and IL-2 were abundantly produced by dermal and epidermal Trm cell subsets (XREF_FIG B and 6C).

      carbon atom activates TNF.

    55. TNF and IL-2 were abundantly produced by dermal and epidermal Trm cell subsets (XREF_FIG B and 6C).

      Trm activates IL2.

    56. Revealing functional specialization among epidermal Trm cells with respect to CD49a expression, CD8 + CD103 + CD49a - Trm cells preferentially produced IL-17, a cytokine required for control of bacterial and fungal infections.

      Trm activates IL17A.

    57. Moreover, IL-17 or IFN-gamma production by distinct Trm cells subsets was generally maintained even in the context of the vigorous tissue inflammation.

      Trm activates IL17A.

    58. In human skin epithelia, CD8 + CD49a + Trm cells produced interferon-gamma, whereas CD8 + CD49a - Trm cells produced interleukin-17 (IL-17).

      Trm activates IL17A.

    59. Corroborating transcriptional profiles, CD8 + CD103 + CD49a - Trm cells produced IL-17 while CD8 + CD103 + CD49a + Trm cells excelled in IFN-gamma production upon stimulation with phorbol 12-myristate 13-acetate and ionomycin (XREF_FIG A-6C).

      Trm activates IL17A.

    60. Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

      Trm activates IL17A.

    61. Here, we identify CD49a expression as a marker delineating a subpopulation ofCD8 + Trm cells in human skin that specifically localize to thebasal layer of epidermis, preferentially produce IFN-gamma, and display high cytotoxic capacity upon stimulation.

      Trm activates IFNG.

    62. Moreover, IL-17 or IFN-gamma production by distinct Trm cells subsets was generally maintained even in the context of the vigorous tissue inflammation.

      Trm activates IFNG.

    63. In human skin epithelia, CD8 + CD49a + Trm cells produced interferon-gamma, whereas CD8 + CD49a - Trm cells produced interleukin-17 (IL-17).

      Trm activates IFNG.

    64. Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

      Trm activates IFNG.

    65. TNF and IL-2 were abundantly produced by dermal and epidermal Trm cell subsets (XREF_FIG B and 6C).

      Trm activates TNF.

    1. The kinase activity of TAK1 leads to phosphorylation events that activate AP-1 and NF-κB. In parallel to cIAP-induced ubiquitination of RIPK2, XIAP’s enzymatic activity results in the formation of polyubiquitin chains on RIPK2, serving as a platform to engage another E3 ligase complex known as the Linear Ubiquitin Assembly Complex (LUBAC) ( xref , xref ).

      RIPK2 is ubiquitinated.

    2. K63-linked ubiquitination of RIPK2 has been established as a means to construct protein scaffolds that transduce downstream signaling.

      RIPK2 is ubiquitinated.

    3. In a step-wise fashion, ubiquitination of RIPK2 leads to activation and recruitment of the TAK1 complex, consisting of TAK1 in association with TAK1-binding protein (TAB)2 and 3.

      RIPK2 is ubiquitinated.

    4. It was recently shown that MAVS recruits NLRP3 to the mitochondria for activation in response to non crystalline activators and that microtubule driven trafficking of the mitochondria is necessary for NLRP3 and ASC complex assembly and activation.

      MAVS translocates to the mitochondrion.

    5. It was recently shown that MAVS recruits NLRP3 to the mitochondria for activation in response to non crystalline activators and that microtubule driven trafficking of the mitochondria is necessary for NLRP3 and ASC complex assembly and activation.

      NLRP3 translocates to the mitochondrion.

    6. By triggering the phosphorylation of the autophagy inducer ULK1, RIPK2 induces autophagy of disrupted mitochondria (mitophagy), preventing the accumulation of ROS and NLRP3 inflammasome activation.

      RIPK2 leads to the phosphorylation of ULK1.

    7. Conversely, others have shown that overexpression of NLRP7 inhibited pro-IL-1beta synthesis and secretion.

      NLRP7 inhibits IL1B.

    8. Some studies have suggested that NLRP12 may negatively regulate the NF-kappaB pathway.

      NLRP12 inhibits NFkappaB.

    9. IFNgamma functions via signal transducer and activator of transcription 1 (STAT1) and can not induce NLRC5 expression in the absence of STAT1.

      IFNG increases the amount of NLRC5.

    10. Despite this focus, much of the nature of the NOD1 and 2 interaction with these structures remains unknown, although recent findings suggest that NOD2 directly binds MDP with high affinity ( xref ), with the N-glycosylated form specific to the mycobacterial cell wall triggering an exceptionally strong immunogenic response compared to N-acetyl MDP ( xref ).

      DPEP1 binds NOD2.

    11. Moreover, it was recently reported that bacterial acylated lipopeptides (acLP) activated NLRP7 and stimulated formation of an NLRP7-ASC-caspase-1 inflammasome ( xref ).

      CASP1 binds PYCARD and NLRP7.

    12. It was recently shown that MAVS recruits NLRP3 to the mitochondria for activation in response to non crystalline activators and that microtubule driven trafficking of the mitochondria is necessary for NLRP3 and ASC complex assembly and activation.

      STS binds NLRP3.

    13. While this mechanism is still poorly understood, the ability of NLRP10 to interact with NOD1 as well as its signaling targets RIPK2, TAK1, and NEMO, suggests that NLRP10 may be involved in optimizing cytokine release following bacterial infections.

      RIPK2 binds NOD1, IKBKG, and MAP3K7.

    14. NOD1 and 2 both interact with RIPK2, via a CARD-CARD homotypic interaction.

      RIPK2 binds NOD1.

    15. In Alzheimer 's disease, amyloid-beta aggregates were shown to activate NLRP3 ex vivo in primary macrophages and microglia.

      APP activates NLRP3.

    16. The possibility of a role for NOD2 in non bacterial infections has also been suggested, with NOD2 having been shown to induce an IFNbeta driven antiviral response following recognition of single stranded viral RNA.

      NOD2 activates IFNB1.

    17. IL-1beta produced downstream of the NLRP3 inflammasome, which is also stimulated by islet amyloid polypeptide, promotes beta-cell dysfunction, and cell death, linking NLRP3 activation to insulin resistance.

      IAPP activates NLRP3.

    18. Moreover, it was recently reported that bacterial acylated lipopeptides (acLP) activated NLRP7 and stimulated formation of an NLRP7-ASC-caspase-1 inflammasome.

      AEBP1 activates NLRP7.

    19. NLRX1 has been shown to enhance ROS production when it is overexpressed, following Chlamydia and Shigella infection, as well as in response to TNFalpha and poly (I : C).
    20. A recent study by Zhong et al. suggested that particulate stimuli might induce mitochondrial production of reactive oxygen species (ROS), which triggers a calcium influx mediated by transient receptor potential melastatin 2 (TRPM2) to activate NLRP3.

      TRPM3 activates NLRP3.

    21. A recent study by Zhong et al. suggested that particulate stimuli might induce mitochondrial production of reactive oxygen species (ROS), which triggers a calcium influx mediated by transient receptor potential melastatin 2 (TRPM2) to activate NLRP3.

      TRPM3 activates calcium(2+).