for - fake meat - Bezos Center for Sustainable Protein

Review coordinated by Life Science Editors Foundation

Reviewed by: Dr. Angela Andersen, Life Science Editors Foundation

Potential Conflicts of Interest: None

Punch line: Activation of the yeast AMP-activated protein kinase (AMPK) negatively regulates MAGIC, inhibits the import of misfolded proteins into mitochondria & promotes mitochondrial biogenesis and fitness.

Why is this interesting? Maybe all those healthy things like caloric restriction, intermittent fasting, exercise etc that activate AMPK & extend lifespan do so by inhibiting MAGIC & preventing mitochondrial damage from misfolded proteins.

Background: Metabolic imbalance & loss of proteostasis are interconnected hallmarks of aging and age-related diseases. A mitochondria-mediated proteostasis mechanism called MAGIC (mitochondria as guardian in cytosol) concentrates cytosolic misfolded protein at the surface of mitochondria, where they are disaggregated by molecular chaperones, and then imported for degradation by mitochondrial proteases. Inhibition of this pathway prolongs protein aggregation in cytosol after proteotoxic stress, but excessive misfolded proteins in mitochondria can lead to mitochondrial damage.

Results: • Genetic screen for MAGIC regulators uncovered 145 genes. Loss of Snf1 (AMPK homolog) led to increased mitochondrial import even without proteotoxic stress. In contrast indirect, constitutive activation of Snf1 (e.g. low glucose) prevented the import of misfolded proteins in mitochondria.

• The data suggest that the reduced accumulation of misfolded proteins in mitochondria of Snf1-active cells is not due to enhanced intramitochondrial degradation nor to reduced levels of the misfolded protein, but rather due to blocked mitochondrial import.

• Deletion of HAP4 counteracted Snf1 activation and overexpression of Hap4 alone recapitulated Snf1 activation. The Hap2/3/4/5 complex activates the expression of nuclear encoded mitochondrial proteins. Their data suggest that high expression of mitochondrial preproteins due to an elevated Snf1-Hap4 axis compete with misfolded proteins for mitochondrial import.

• Proteotoxic stress led to a reduced growth rate & reduced mitochondrial fitness in high glucose medium but not under glucose limitation. The data suggest that low glucose, activation of Snf1 & prevention of misfolded protein import into mitochondria prevent the growth defect.

• Many neurodegenerative disease-associated aggregation-prone proteins (α-synuclein, FUSP525L, TDP-43, amyloid beta, C9ORF72-associated poly(GR) dipeptide) are detected in mitochondria of human patients or disease models and impair mitochondrial functions. Their data suggest that the import of α-synuclein & associated reduction in mitochondrial fitness can be counteracted by indirect AMPK/Snf1 activation (i.e. glucose limitation).

• Show data in yeast & human cells.

Discussion: This paper revealed an unexpected link between cellular metabolism and proteostasis through MAGIC/mitochondria.

• Snf1/AMPK is a key regulator of MAGIC & of misfolded protein import into mitochondria.

• Snf1/AMPK balances the mitochondrial metabolic and proteostatic functions in response to glucose availability and protects mitochondrial fitness under proteotoxic stress.

• The authors speculate that in high glucose, cells rely on glycolysis for ATP production and mitochondria ‘moonlighting’ in cellular proteostasis through MAGIC, but when glucose is limited and cells rely on oxidative phosphorylation for ATP generation, AMPK is activated and shuts down MAGIC, prioritizing the import of essential mitochondrial preproteins to ensure mitochondrial fitness and energy production.

• Acknowledge limitations: Snf1/Hap4 activation elevates the expression of hundreds of mitochondrial preproteins, not clear whether specific preproteins or cytosolic factors directly involved in inhibiting mitochondrial import, & that more details on mechanisms will be of interest.

• Caloric restriction & AMPK activation might contribute to lifespan extension by inhibiting MAGIC. In human, AMPK activity is elevated during health-benefitting activities such as exercise. Their data suggest that elevating AMPK activity may be beneficial in alleviating proteotoxicity associated with degenerative diseases - but hyperactivated AMPK has also been reported in several neurodegenerative diseases with proteostasis decline (Ang wonders- maybe AMPK is overwhelmed?).

THIS IS A GORGEOUS PAPER!

Future work - I can't wait to see the characterization of the ribosome biogenesis genes that they also pulled out as MAGIC regulators. Anticipating a translation, misfolded protein, mitochondria, aging axis :)

protein

examples of high protein (hard) wheats: - Khorasan - Durum - Hard White Wheat - Hard Red Wheat - Red Fife

Good for breads, pizza, and things where chew is more valuable.

examples of lower protein (soft) wheats: - Sonora - Spelt - Soft White - Soft Red - Einkorn

good for pastries, cakes, cookies, etc.

Review coordinated by Life Science Editors Foundation

Reviewed by: Dr. Angela Andersen

Potential Conflicts of Interest: None

Background: * mRNAs in polarized cells often have a distinct spatial localization patterns that enable localized protein production * In non-polarized cells, mRNAs encoding membrane and secretory proteins are predominantly translated on the endoplasmic reticulum (ER), some mRNAs are enriched on the mitochondrial surface, some mRNAs are bound to the RNA-binding protein (RBP) TIS11B at the surface of the rough ER in "TIS granules". * The translation of specific mRNAs in TIS granules allows assembly of protein complexes that cannot be established when the mRNAs are translated on the ER but outside of TIS granules (physiological relevance). * The canonical rough ER (CRER) is distinct from the TIS granule ER (TGER), and both are distinct from the cytosol.

Questions: * Do mRNAs that encode non-membrane proteins differentially localize to the ER or the cytosol? (in steady state) * Does the amount of protein synthesis differ depending on the subcytoplasmic location of an mRNA?

Summary: * A third of mRNAs that encode non-membrane proteins have a biased localization to TGER or CRER, indicating that the ER membrane is a general site of translation for both membrane and non-membrane proteins. * 52% of mRNAs that encode non-membrane proteins have a biased mRNA transcript localization pattern towards a single cytoplasmic compartment. the TGER, CRER or cytosol. * The localization at the TGER or CRER was largely controlled by a combinatorial code of AU-RBPs at the 3'UTR. TIS11B promotes mRNA localization to TGER and TIA1/L1 to CRER. * LARP4B bound to the 3'UTR promotes cytosolic localization. * The location of translation has an independent effect on protein levels independent of the RBPs/3'UTR: redirecting cytosolic mRNAs to the rough ER membrane increased their steady-state protein levels by two-fold, indicating that the ER environment promotes protein expression. * Compartment-enriched mRNAs differed in their mRNA production and degradation rates, as well as functional classes and levels of their encoded proteins. Therefore the cytoplasm is partitioned into different functional and regulatory compartments that are not enclosed by membranes. * low-abundance proteins are translated in the TGER region. mRNAs encoding zinc finger proteins and transcription factors were substantially enriched at the TGER. These gene classes are usually expressed at lower levels than others.. This localization may regulate protein complex assembly (membrane proteins that are translated in the TGER domain establish protein complexes that cannot be formed when the proteins are translated on the CRER). The TGER may ensure that low-abundance mRNAs are effectively translated into low-abundance proteins. * mRNAs that are the most stable and encode the most highly expressed proteins are enriched on the CRER and include helicases, cytoskeleton-bound proteins, and chromatin regulators, overturning the idea that most non-membrane protein-encoding mRNAs are translated in the cytosol. * mRNAs overrepresented in the cytosol had the highest production and degradation rates and were enriched in proteins involved in mRNA processing and translation factors, whose abundance levels require tight control.

Advance: Evidence for functional compartmentalization of non-membrane mRNA protein expression in the cytosol vs ER. In steady state, general localization of mRNAs to the ER promotes high protein levels.

Significance: Engineered 3'UTR sequences could potentially boost protein expression by localizing mRNAs to the ER in experimental settings, for vaccines etc.

Remaining questions/points: * How does the rough ER stimulate protein expression? * Does the mRNA localization affect complex formation and/or function of non-membrane proteins? * Does this occur in cells other than HEK293T? * Is this regulated?

Nuclear pore complex or NPC. There is a size exclusion. <60kDa to pass through unassisted.

As soon as this sequence is translated, the SRP binds it. Elongation is temporarily arrested. SRP-ribosome complex binds to the SRP receptor on the ER membrane. Translation now continues into the lumen of the ER. The SPR and its receptor are recycled.

What gives Amino acids their specific special properties?

How are peptide bonds formed? What is released?

What is a peptide bond?

What is the core sequence to a protein structure? Which letters are the Terminus and which is the alpha C?

What is in a protein structure

What are Amino Acids?

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Ag can bind with protein at Cys, His and Met residues.

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by attaching acceptor and donor to different domains of a target protein, the interdomain dynamics can be monitored

The entirety of proteins that are expressed as a cell, tissue or an organism.

This is the process of a complementary mRNA copy of a single gene on the DNA that is created in the nucleus. The mRNA is smaller than the DNA so it can carry the genetic code into the ribosome and into the cytoplasm that enables the protein creation.

This is a single strand on an RNA molecule that leaves the the nucleus of a cell in order to relocate to the cytoplasm. This is where the mRNA can help create the protein for the cell in a process known as protein synthesis. The mRNA takes in information passed into it by DNA and decode it for the ribosomes to make more protein for the cell to live on.

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Experiment was performed using purified delftibactin, not whole cell Delftia. While this helps eliminate variables, we must make sure isolation and purification has no effect on protein function.

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Pay attention. ER Stress, and the Integrated Stress Response as well as Unfolded Protein Response

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