Hsp70 Targets a Cytoplasmic Quality Control Substrate to the San1p Ubiquitin Ligase

Guerriero, Christopher J.; Weiberth, Kurt F.; Brodsky, Jeffrey L.

doi:10.1074/jbc.m113.475905

Cited by 76 publications

(115 citation statements)

References 96 publications

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“…In this context, cytosolic proteasomes are indispensable for yeast growth, whereas nuclear proteasomes are essential for viability (Tsuchiya et al, 2013). Additionally, there is growing evidence that diverse cytosolic proteins are translocated to the nucleus and are degraded by nuclear proteasomes through chaperone-dependent delivery and ubiquitylation by the nuclear E3 ubiquitin ligase San1 (Guerriero et al, 2013;Heck et al, 2010;Park et al, 2013;Prasad et al, 2010). Hence, the discovery that multiple INMAD pathways exist bolsters the notion that the nuclear compartment is well equipped as a major site for protein quality control.…”

Section: Discussionmentioning

confidence: 99%

Cdc48 and Ubx1 participate in a pathway associated with the inner nuclear membrane that governs Asi1 degradation

Pantazopoulou

Boban

Foisner

et al. 2016

Journal of Cell Science

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The nuclear envelope is a barrier comprising outer and inner membranes that separate the cytoplasm from the nucleoplasm. The two membranes have different physical characteristics and protein compositions. The processes governing the stability of inner nuclear membrane (INM) proteins are not well characterized. In Saccharomyces cerevisiae, the INM Asi1-Asi3 complex, principally composed of integral membrane proteins Asi1 and Asi3, is an E3 ubiquitin ligase. In addition to its well-documented function in endoplasmic reticulum (ER)-associated degradation, the Doa10 E3 ubiquitin ligase complex partially localizes to the INM. The Asi1-Asi3 and Doa10 complexes define independent INM-associated degradation (INMAD) pathways that target discrete sets of nuclear substrates for proteasomal degradation. Here, we report that Asi1 is rapidly turned over (t 1/2 ≤30 min). Its turnover depends on ubiquitinmediated degradation by nucleus-localized proteasomes, exhibiting a clear requirement for the E2 ubiquitin-conjugating enzyme Ubc7, Cue1 and the AAA ATPase Cdc48 and co-factor Ubx1. Asi1 turnover occurs largely independently of the Asi1-Asi3 or Doa10 complexes, indicating that it is subject to quality control at the INM in a manner distinct from that of the characterized INMAD pathways.

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Section: Discussionmentioning

confidence: 99%

Cdc48 and Ubx1 participate in a pathway associated with the inner nuclear membrane that governs Asi1 degradation

Pantazopoulou

Boban

Foisner

et al. 2016

Journal of Cell Science

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“…Perhaps surprisingly, beyond nuclear misfolded proteins, multiple cytoplasmic misfolded proteins also appear to be actively targeted to the nucleus for degradation. Studies indicate that this targeting is dependent on Hsp70/Ssa1 [80, 81, 87], as well as the DNAJ co-chaperone Sis1 and the RanGTP gradient [92]. A similar situation for cytoplasmic misfolded polypeptides has been described in mammalian cells, where a model misfolded protein, mutant firefly luciferase, is proposed to be imported into the nucleus by the Sis1 ortholog DNAJB1 for degradation [92].…”

Section: Ups In the Nucleusmentioning

confidence: 96%

“…Doa10 also recognizes N-terminally acetylated proteins as part of the N-end rule pathway, but how this contributes to nuclear proteostasis is unexplored [86]. Of the substrates tested, those recognized by San1 and Doa10 do not widely overlap (reviewed in [80]), and Doa10 may preferentially recognize misfolding of integral membrane proteins [87]. …”

Section: Ups In the Nucleusmentioning

confidence: 99%

“…The targeting ability of Hsp70/Ssa1 depends on its ATPase activity, requiring the nucleotide exchange factor Hsp110/Sse1 and the Hsp40 co-chaperones Ydj1 and/or Sis1 (reviewed in [80]). Sis1 may have additional roles targeting misfolded cytoplasmic substrates to the nucleus for degradation [92].…”

Section: Ups In the Nucleusmentioning

confidence: 99%

“…For San1, Hsp70/Ssa1facilitates this E3 ligase’s ability to bind at least one substrate [80]. Other studies indicate that chaperones do not readily interact with San1 [78].…”

Section: Ups In the Nucleusmentioning

confidence: 99%

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How the Nucleus Copes with Proteotoxic Stress

Shibata

Morimoto

2014

Current Biology

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Summary The proper folding of proteins is continuously challenged by intrinsic and extrinsic stresses, and the accumulation of toxic misfolded proteins is associated with many human diseases. Eukaryotic cells have evolved a complex network of protein quality control pathways to protect the proteome, and these pathways are specialized for each subcellular compartment. While many details have been elucidated for how the cytosol and endoplasmic reticulum counteract proteotoxic stress, relatively little is known about the pathways protecting the nucleus from protein misfolding. Here, we offer a conceptual framework for how proteostasis is maintained in this organelle. We define the particular requirements that must be considered for the nucleus to manage proteotoxic stress, summarize the known and implicated pathways of nuclear protein quality control, and identify the unresolved questions in the field. Proper maintenance of nuclear proteostasis has important implications in preserving genomic integrity, as well as for aging and disease.

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Molecular mass as a determinant for nuclear San1‐dependent targeting of misfolded cytosolic proteins to proteasomal degradation

Amm

Wolf

2016

FEBS Letters

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Most misfolded cytosolic proteins in the cell are eliminated by the ubiquitin-proteasome system. In yeast, polyubiquitination of misfolded cytosolic proteins is triggered mainly by the action of two ubiquitin ligases Ubr1, formerly discovered as recognition component of the N-end rule pathway, and the nuclear ubiquitin ligase San1. For San1-mediated targeting to proteasomal degradation, cytosolic proteins have to be imported into the nucleus. Selection of misfolded substrates for import into the nucleus had remained elusive. This study shows that an increasing molecular mass of substrates prevents nuclear San1-triggered proteasomal degradation but renders them susceptible to cytoplasmic Ubr1-triggered degradation.

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Hsp70 Targets a Cytoplasmic Quality Control Substrate to the San1p Ubiquitin Ligase

Cited by 76 publications

References 96 publications

Cdc48 and Ubx1 participate in a pathway associated with the inner nuclear membrane that governs Asi1 degradation

Cdc48 and Ubx1 participate in a pathway associated with the inner nuclear membrane that governs Asi1 degradation

How the Nucleus Copes with Proteotoxic Stress

Molecular mass as a determinant for nuclear San1‐dependent targeting of misfolded cytosolic proteins to proteasomal degradation

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