Robust Glyoxalase activity of Hsp31, a ThiJ/DJ-1/PfpI Family Member Protein, Is Critical for Oxidative Stress Resistance in Saccharomyces cerevisiae

Bankapalli, Kondalarao; Saladi, SreeDivya; Awadia, Sahezeel; Goswami, Arvind Vittal; Samaddar, Madhuja; D’Silva, Patrick

doi:10.1074/jbc.m115.673624

Cited by 76 publications

(87 citation statements)

References 91 publications

(85 reference statements)

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“…5E, F, Tables S8, S9). We identified a decrease in abundance of the stress response chaperone Hsp31 (the yeast homolog of the Parkinson's Disease associated human DJ-1 40,41 ) in the Cdc48-C115S strain at 24h, as well as oxidative stress associated proteins such as the thioredoxin Trx1 and the peroxiredoxin Tsa1 at 48h, strengthening our understanding that Cdc48-C115S may have altered redox regulation. Importantly, we also identified a decreased association between the mutant Cdc48 and the Ubxfamily member Shp1/Ubx1 at 48h.…”

Section: Mutation In Cys115 Alters Cdc48 Interactome Reflecting Diffmentioning

confidence: 53%

A molecular switch for Cdc48 activity and localization during oxidative stress and aging

Reichmann

Radzinski

Yogev

et al. 2019

Preprint

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Control over a healthy proteome begins with the birth of the polypeptide chain and ends with coordinated protein degradation. One of the major players in eukaryotic protein degradation is the essential and highly conserved ATPase, Cdc48 (p97/VCP in mammals). Cdc48 mediates clearance of misfolded proteins from the nucleus, cytosol, ER, mitochondria, and more. Here we dissect the crosstalk between cellular oxidation and Cdc48 activity by identification of a redox-sensitive site, Cys115. By integrating proteomics, biochemistry, microscopy, and bioinformatics, we show that removal of Cys115's redox-sensitive thiol group leads to accumulation of Cdc48 in the nucleus and consequently, results in severe defects in the oxidative stress response, mitochondrial fragmentation, and a decrease in ERAD and sterol biogenesis. We have thus identified a unique redox switch in Cdc48, which may provide a clearer picture of the importance of Cdc48's localization in maintaining a "healthy" proteome during oxidative stress and chronological aging in yeast.

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Section: Mutation In Cys115 Alters Cdc48 Interactome Reflecting Diffmentioning

confidence: 53%

A molecular switch for Cdc48 activity and localization during oxidative stress and aging

Reichmann

Radzinski

Yogev

et al. 2019

Preprint

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“…Visualization of mitochondria and analysis of mtDNA stability were performed as described previously (84)(85)(86). To visualize mitochondria, the yeast cells were transformed with pRS415 vector containing presequence of subunit 9 (pSU9) followed by mCherry fluorescent protein, which decorates the mitochondria exclusively.…”

Section: Methodsmentioning

confidence: 99%

“…Isolation of mitochondria and precursor accumulation analysis (Hsp60) were performed as described in previously published protocols (22). Measurement of ROS was carried out as described earlier (84). The antisera used for immunodecoration against yeast-specific proteins, such as Hsp60, Mge1, Ydj1, Tim23, Tim17, Tim50, Tim44, Pam18, and Pam16 were raised in rabbits, as reported earlier (22).…”

Section: Methodsmentioning

confidence: 99%

Role of Tim17 Transmembrane Regions in Regulating the Architecture of Presequence Translocase and Mitochondrial DNA Stability

Matta

Pareek

Bankapalli

et al. 2017

Molecular and Cellular Biology

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Mitochondrial life cycle and protein import are intricate cellular processes, which require precise coordination between the transport machineries of outer and inner mitochondrial membranes. Presequence translocase performs the indispensable function of translocating preproteins having N-terminal targeting sequences across the inner membrane. Tim23 forms the core of the voltage-gated import channel, while Tim17 is presumed to maintain the stoichiometry of the translocase. However, mechanistic insights into how Tim17 coordinates these regulatory events within the complex remained elusive. We demonstrate that Tim17 harbors conserved G/AXXXG/A motifs within its transmembrane regions and plays an imperative role in the translocase assembly through interaction with Tim23. Tandem motifs are highly essential, as most of the amino acid substitutions lead to nonviability due to the complete destabilization of the TIM23 channel. Importantly, Tim17 transmembrane regions regulate the dynamic assembly of translocase to form either the TIM23 (PAM)-complex or TIM23 (SORT)-complex by recruiting the presequence translocase-associated motor (PAM) machinery or Tim21, respectively. To a greater significance, tim17 mutants displayed mitochondrial DNA (mtDNA) instability, membrane potential loss, and defective import, resulting in organellar dysfunction. We conclude that the integrity of Tim17 transmembrane regions is critical for mitochondrial function and protein turnover.KEYWORDS mitochondria, presequence translocase, mtDNA stability, preprotein import, membrane potential T he vast majority of mitochondrial proteins are encoded by nuclear genes and synthesized on cytosolic ribosomes with an amino-terminal positively charged cleavable signal sequence. The efficient import of mitochondrial proteins requires precise coordination between the translocases of the outer membrane (TOM complex) and the inner membrane (TIM23 complex) (1-9). After initial recognition and transport through TOM complex, these preproteins are actively sorted based on their destination. The preproteins directed toward the matrix compartment possess an N-terminal positively charged presequence and are imported into the matrix compartment with the aid of presequence translocase (TIM23 complex) (1-10). The core of presequence translocase consists of a membrane-bound channel component formed by . Tim23 and Tim17 are phylogenetically related integral membrane proteins and have similar transmembrane topology. Tim23 contributes to the formation of voltage-gated protein-conducting pores, while the evidence suggests that Tim17 is majorly involved in regulating the channel activity (16)(17)(18)(19)(20)(21)(22)(23). Other components such as Tim50 and Tim21 act as receptors and coordinate with the intermembrane space (IMS) domain of Tim23 to facilitate preprotein recognition and transfer from the TOM complex to presequence translocase (16, 17, 22, 24-32). Mgr2 has been recently

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“…More recently, Hsp31, a member of the DJ-1 superfamily (compare chapter on MG in Drosophila), was also found to possess glyoxalase activity in vitro [92]. Strains in which Hsp31 was deleted exhibited increased sensitivity to exogenously added MG.…”

Section: Cellular Detoxification Of Mg and Its Regulation In Yeastmentioning

confidence: 99%

Effects of the Reactive Metabolite Methylglyoxal on Cellular Signalling, Insulin Action and Metabolism – What We Know in Mammals and What We Can Learn From Yeast

Zemva

Pfaff

Groener

et al. 2018

Exp Clin Endocrinol Diabetes

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Levels of reactive metabolites such as reactive carbonyl and oxygen species are increased in patients with diabetes mellitus. The most important reactive dicarbonyl species, methylglyoxal (MG), formed as by-product during glucose metabolism, is more and more recognized as a trigger for the development and progression of diabetic complications. Although it is clear that MG provokes toxic effects, it is currently not well understood what cellular changes MG induces on a molecular level that may lead to pathophysiological conditions found in long-term diabetic complications. Here we review the current knowledge about the molecular effects that MG can induce in a cell. Within the mammalian system, we will focus mostly on the metabolic effects MG exerts when applied systemically to rodents or when applied to pancreatic β-cells and adipocytes. Due to the common limitations associated with complex model organisms, we then summarize how yeast as a very simple model organism can help to gain valuable comprehensive information on general defence pathways cells exert in response to MG stress. Pioneering studies in additional rather simple eukaryotic model organisms suggest that many cellular reactions in response to MG are highly conserved throughout evolution.

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Robust Glyoxalase activity of Hsp31, a ThiJ/DJ-1/PfpI Family Member Protein, Is Critical for Oxidative Stress Resistance in Saccharomyces cerevisiae

Cited by 76 publications

References 91 publications

A molecular switch for Cdc48 activity and localization during oxidative stress and aging

A molecular switch for Cdc48 activity and localization during oxidative stress and aging

Role of Tim17 Transmembrane Regions in Regulating the Architecture of Presequence Translocase and Mitochondrial DNA Stability

Effects of the Reactive Metabolite Methylglyoxal on Cellular Signalling, Insulin Action and Metabolism – What We Know in Mammals and What We Can Learn From Yeast

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