Proteomic Analysis Identifies Ribosome Reduction as an Effective Proteotoxic Stress Response

Guerra-Moreno, Ángel; Isasa, Marta; Bhanu, Meera K.; Waterman, David P.; Eapen, Vinay V.; Gygi, Steven P.; Hanna, John

doi:10.1074/jbc.m115.684969

Cited by 58 publications

(144 citation statements)

References 40 publications

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“…Cuz1, the other AN1 zinc finger protein, appears to function in protein degradation via direct interaction with the proteasome and Cdc48 (17,18). Cuz1 protein is specifically induced by trivalent arsenic (11,17), which is of interest because accumulating evidence suggests that a major aspect of toxicity of trivalent arsenic relates to protein misfolding (9 -11, 20).…”

Section: Dynamic Regulation Of Tmc1 Protein In Response Tomentioning

confidence: 99%

“…We recently reported a proteomic characterization of the cellular response to trivalent arsenic (11). Using a tandem mass tag-based (TMT) 2 multiplexed mass spectrometry method, we were able to determine the relative protein abundance of nearly 4,600 proteins (of ϳ6,000 predicted in Saccharomyces cerevisiae).…”

Section: Dynamic Regulation Of Tmc1 Protein In Response Tomentioning

confidence: 99%

“…In the absence of sodium arsenite, Tmc1 levels were difficult to detect above background and showed no spe- . The data were generated using a TMT-based mass spectrometry proteomic approach (11). The data shown represent endogenous untagged Tmc1 protein.…”

Section: Dynamic Regulation Of Tmc1 Protein In Response Tomentioning

confidence: 99%

“…By contrast, mutants defective in protein synthesis are frequently resistant to this drug. This includes not only mutants in components of the ribosome proper but also mutants in ribosome biogenesis and other pathways that positively regulate protein synthesis (10,11). This latter finding has been suggested to reflect a preferential role for arsenic in misfolding of newly synthesized proteins (9,11).…”

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confidence: 99%

“…Under conditions that compromise or overwhelm proteasome function, Rpn4 protein is stabilized, leading to increased Rpn4 transcriptional activity that promotes new proteasome synthesis until proteasome function is restored to levels adequate to again carry out rapid Rpn4 degradation. This homeostatic feedback pathway is crucial for cells to survive diverse stresses arising from misfolded proteins, and indeed Rpn4 protein levels are markedly increased after treatment with sodium arsenite (11).…”

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confidence: 99%

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Tmc1 Is a Dynamically Regulated Effector of the Rpn4 Proteotoxic Stress Response

Guerra-Moreno

Hanna

2016

Journal of Biological Chemistry

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The ubiquitin-proteasome system represents the major pathway of selective intracellular protein degradation in eukaryotes. Misfolded proteins represent an important class of substrates for this pathway, and the failure to destroy misfolded proteins is associated with a number of human diseases. The transcription factor Rpn4 mediates a key proteotoxic stress response whose best known function is to control proteasome abundance by a homeostatic feedback mechanism. Here we identify the uncharacterized zinc finger protein Tmc1 as a dynamically regulated stress-responsive protein. Rpn4 induces TMC1 transcription in response to misfolded proteins. However, this response is counteracted by rapid proteasome-dependent degradation of Tmc1, which serves to normalize Tmc1 protein levels after induction. Precise control of Tmc1 levels is needed in vivo to survive multiple stressors related to proteostasis. Thus, Tmc1 represents a novel effector and substrate of the Rpn4 proteotoxic stress response.

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Section: Dynamic Regulation Of Tmc1 Protein In Response Tomentioning

confidence: 99%

Section: Dynamic Regulation Of Tmc1 Protein In Response Tomentioning

confidence: 99%

Section: Dynamic Regulation Of Tmc1 Protein In Response Tomentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Tmc1 Is a Dynamically Regulated Effector of the Rpn4 Proteotoxic Stress Response

Guerra-Moreno

Hanna

2016

Journal of Biological Chemistry

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Regulation of the unfolded protein response in yeast by oxidative stress

et al. 2019

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In the unfolded protein response (UPR), Ire1 activates Hac1 to coordinate the transcription of hundreds of genes to mitigate ER stress. Recent work in Caenorhabditis elegans suggests that oxidative stress inhibits this canonical Ire1 signalling pathway, activating instead an antioxidant stress response. We sought to determine whether this novel mode of UPR function also existed in yeast, where Ire1 has been best characterized. We show that the yeast UPR is also subject to inhibition by oxidative stress. Inhibition is mediated by a single evolutionarily conserved cysteine, and affects both luminal and membrane pathways of Ire1 activation. In yeast, Ire1 appears dispensable for resistance to oxidative stress and, therefore, the physiological significance of this pathway remains to be demonstrated.

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Yeast chaperones and ubiquitin ligases contribute to proteostasis during arsenite stress by preventing or clearing protein aggregates

et al. 2023

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Arsenite causes proteotoxicity by targeting nascent proteins for misfolding and aggregation. Here, we assessed how selected yeast chaperones and ubiquitin ligases contribute to proteostasis during arsenite stress. Loss of the ribosome‐associated chaperones Zuo1, Ssz1, and Ssb1/Ssb2 reduced global translation and protein aggregation, and increased arsenite resistance. Loss of cytosolic GimC/prefoldin function led to defective aggregate clearance and arsenite sensitivity. Arsenite did not induce ribosomal stalling or impair ribosome quality control, and ribosome‐associated ubiquitin ligases contributed little to proteostasis. Instead, the cytosolic ubiquitin ligase Rsp5 was important for aggregate clearance and resistance. Our study suggests that damage prevention, by decreased aggregate formation, and damage elimination, by enhanced aggregate clearance, are important protective mechanisms that maintain proteostasis during arsenite stress.

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Proteomic Analysis Identifies Ribosome Reduction as an Effective Proteotoxic Stress Response

Cited by 58 publications

References 40 publications

Tmc1 Is a Dynamically Regulated Effector of the Rpn4 Proteotoxic Stress Response

Tmc1 Is a Dynamically Regulated Effector of the Rpn4 Proteotoxic Stress Response

Regulation of the unfolded protein response in yeast by oxidative stress

Yeast chaperones and ubiquitin ligases contribute to proteostasis during arsenite stress by preventing or clearing protein aggregates

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