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On the edge of degradation: Autophagy regulation by RNA decay

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Cells must dynamically adapt to altered environmental conditions, particularly during times of stress, to ensure their ability to function effectively and survive. The macroautophagy/autophagy pathway is highly conserved across eukaryotic cells and promotes cell survival during stressful conditions. In general, basal autophagy occurs at a low level to sustain cellular homeostasis and metabolism. However, autophagy is robustly upregulated in response to nutrient deprivation, pathogen infection and increased accumulation of potentially toxic protein aggregates and superfluous organelles. Within the cell, RNA decay maintains quality control to remove aberrant transcripts and regulate appropriate levels of gene expression. Recent evidence has identified components of the cellular mRNA decay machinery as novel regulators of autophagy. Here, we review current findings that demonstrate how autophagy is modulated through RNA decay. This article is categorized under: RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Turnover and Surveillance > Regulation of RNA Stability
An overview of autophagy in the yeast Saccharomyces cerevisiae. Following induction by either starvation or treatment with rapamycin, inactivation of TOR triggers autophagy. TOR/MTOR is a serine/threonine kinase and major negative regulator of autophagy (Noda & Ohsumi, ). In a stepwise mechanism in yeast, the phagophore nucleates at the perivacuolar phagophore assembly site (PAS). The phagophore expands to envelope proximal cytoplasmic cargo; this process requires 2 conserved Ubl‐conjugation systems: Atg12 (consisting of Atg5, Atg7, Atg10, Atg12 and Atg16) and Atg8 (including Atg3, Atg4, Atg7 and Atg8). The phagophore closes and matures to form the complete double‐membrane autophagosome. Atg4 has multiple roles, including proteolytic processing of Atg8 at its C‐terminus during early autophagy. A second Atg4‐mediated cleavage event subsequently deconjugates Atg8 from the autophagosome outer membrane (Kirisako et al., ; Nair et al., ). Fusion of the autophagosome with the vacuole is mediated by proteins such as the SNARE Vam7 (Liu et al., ). Atg15 is required for the degradation of autophagic body membranes, allowing subsequent degradation of the sequestered cargo by vacuolar hydrolases. The current data demonstrate an efflux model for amino acids into the cytosol (Yang, Huang, Geng, Nair, & Klionsky, ); however, products resulting from RNA catabolism are released from the cell (Huang et al., ), and the mechanisms used for the efflux of metabolic byproducts of other macromolecules (carbohydrates and lipids) have yet to be identified
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ATG regulation by 5′ to 3′ mRNA decay. (a) During nutrient‐rich conditions in yeast, TORC1 performs multiple roles in autophagy inhibition. Rim15 (a positive regulator of autophagy) is inhibited by major cellular nutrient sensors TORC1 and protein kinase A (PKA). TORC1 phosphorylates the catalytic decapping factor Dcp2. Dcp2 (in conjunction with Dcp1) negatively regulates autophagy by targeting ATG transcripts for decapping. At the same time, the decapping stimulatory factor Dhh1 and the exonuclease Xrn1 negatively regulate select autophagy transcripts. (b) Autophagy induction by nutrient‐starvation (or rapamycin treatment for Igo1/2) inactivates TORC1, enabling Rim15 to phosphorylate Igo1/2. Igo1/2 phosphorylation promotes its association with Dhh1, thereby protecting transcripts from RNA decay. Whether Igo1/2 associates with Dhh1 to influence ATG transcripts during nitrogen starvation remains to be investigated. Canonical 5′ to 3′ RNA decay components Dcp2 and Xrn1 are downregulated during nitrogen starvation. During starvation, select ATG mRNAs (which are targeted for decay by Dhh1, Dcp2 and Xrn1 under nutrient‐replete conditions) are no longer marked for degradation and are instead likely translated to promote autophagy. For clarity, the physical interaction between Dcp2 and the C‐terminal region of Dhh1 (Decker et al., ) is not depicted here
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Canonical mRNA decay pathways. RNA decay pathways are essential for regulating gene expression post‐transcriptionally. The 2 major pathways controlling mRNA degradation occur in either the 5′ to 3′ (left) or the 3′ to 5′ (right) direction by the multisubunit exosome. During canonical 5′ to 3′ RNA decay, transcripts undergo deadenylation and decapping by the Dcp2 catalytic complex followed by Xrn1‐mediated hydrolysis. After 3′ deadenylation, the multisubunit exosome complex degrades transcripts in the 3′ to 5′ direction
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RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms

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