Compartment-specific aggregases direct distinct nuclear and cytoplasmic aggregate deposition

Stephanie Bm Miller; Chi-Ting Ho; Juliane Winkler; Maria Khokhrina; Annett Neuner; Mohamed Yh Mohamed; D Lys Guilbride; Karsten Richter; Michael Lisby; Elmar Schiebel; Axel Mogk; Bernd Bukau

doi:10.15252/embj.201489524

Compartment-specific aggregases direct distinct nuclear and cytoplasmic aggregate deposition

Stephanie Bm Miller, Chi-Ting Ho, Juliane Winkler, Maria Khokhrina, Annett Neuner, Mohamed Yh Mohamed, D Lys Guilbride, Karsten Richter, Michael Lisby, Elmar Schiebel, Axel Mogk, Bernd Bukau

Functional Genomics

146 Citations (Scopus)

Abstract

Disruption of the functional protein balance in living cells activates protective quality control systems to repair damaged proteins or sequester potentially cytotoxic misfolded proteins into aggregates. The established model based on Saccharomyces cerevisiae indicates that aggregating proteins in the cytosol of eukaryotic cells partition between cytosolic juxtanuclear (JUNQ) and peripheral deposits. Substrate ubiquitination acts as the sorting principle determining JUNQ deposition and subsequent degradation. Here, we show that JUNQ unexpectedly resides inside the nucleus, defining a new intranuclear quality control compartment, INQ, for the deposition of both nuclear and cytosolic misfolded proteins, irrespective of ubiquitination. Deposition of misfolded cytosolic proteins at INQ involves chaperone-assisted nuclear import via nuclear pores. The compartment-specific aggregases, Btn2 (nuclear) and Hsp42 (cytosolic), direct protein deposition to nuclear INQ and cytosolic (CytoQ) sites, respectively. Intriguingly, Btn2 is transiently induced by both protein folding stress and DNA replication stress, with DNA surveillance proteins accumulating at INQ. Our data therefore reveal a bipartite, inter-compartmental protein quality control system linked to DNA surveillance via INQ and Btn2. Synopsis 'Juxtanuclear' deposits of misfolded protein in fact reside in a new intranuclear quality control compartment (INQ). INQ formation is dependent on Btn2, while cytosolic protein deposition is mediated by the Hsp42 aggregase. Proteotoxic stress in yeast results in organized sequestration of misfolded proteins at cytosolic CytoQ and nuclear INQ (former JUNQ) deposition sites. INQ deposition does not rely on substrate ubiquitination and does not target sequestered proteins for degradation. CytoQ and INQ formation relies on compartment-specific aggregases, the cytosolic Hsp42 and the nuclear Btn2. DNA replication stress triggers Btn2-dependent protein sequestration, linking cellular mechanisms coping with protein and DNA stress. 'Juxtanuclear' deposits of misfolded protein in fact reside in a new intranuclear quality control compartment (INQ). INQ formation is dependent on Btn2, while cytosolic protein deposition is mediated by the Hsp42 aggregase.

Original language	English
Journal	E M B O Journal
Volume	34
Issue number	6
Pages (from-to)	778-797
Number of pages	20
ISSN	0261-4189
DOIs	https://doi.org/10.15252/embj.201489524
Publication status	Published - 12 Mar 2015

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title = "Compartment-specific aggregases direct distinct nuclear and cytoplasmic aggregate deposition",

abstract = "Disruption of the functional protein balance in living cells activates protective quality control systems to repair damaged proteins or sequester potentially cytotoxic misfolded proteins into aggregates. The established model based on Saccharomyces cerevisiae indicates that aggregating proteins in the cytosol of eukaryotic cells partition between cytosolic juxtanuclear (JUNQ) and peripheral deposits. Substrate ubiquitination acts as the sorting principle determining JUNQ deposition and subsequent degradation. Here, we show that JUNQ unexpectedly resides inside the nucleus, defining a new intranuclear quality control compartment, INQ, for the deposition of both nuclear and cytosolic misfolded proteins, irrespective of ubiquitination. Deposition of misfolded cytosolic proteins at INQ involves chaperone-assisted nuclear import via nuclear pores. The compartment-specific aggregases, Btn2 (nuclear) and Hsp42 (cytosolic), direct protein deposition to nuclear INQ and cytosolic (CytoQ) sites, respectively. Intriguingly, Btn2 is transiently induced by both protein folding stress and DNA replication stress, with DNA surveillance proteins accumulating at INQ. Our data therefore reveal a bipartite, inter-compartmental protein quality control system linked to DNA surveillance via INQ and Btn2. Synopsis 'Juxtanuclear' deposits of misfolded protein in fact reside in a new intranuclear quality control compartment (INQ). INQ formation is dependent on Btn2, while cytosolic protein deposition is mediated by the Hsp42 aggregase. Proteotoxic stress in yeast results in organized sequestration of misfolded proteins at cytosolic CytoQ and nuclear INQ (former JUNQ) deposition sites. INQ deposition does not rely on substrate ubiquitination and does not target sequestered proteins for degradation. CytoQ and INQ formation relies on compartment-specific aggregases, the cytosolic Hsp42 and the nuclear Btn2. DNA replication stress triggers Btn2-dependent protein sequestration, linking cellular mechanisms coping with protein and DNA stress. 'Juxtanuclear' deposits of misfolded protein in fact reside in a new intranuclear quality control compartment (INQ). INQ formation is dependent on Btn2, while cytosolic protein deposition is mediated by the Hsp42 aggregase.",

author = "Miller, {Stephanie Bm} and Chi-Ting Ho and Juliane Winkler and Maria Khokhrina and Annett Neuner and Mohamed, {Mohamed Yh} and Guilbride, {D Lys} and Karsten Richter and Michael Lisby and Elmar Schiebel and Axel Mogk and Bernd Bukau",

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doi = "10.15252/embj.201489524",

language = "English",

volume = "34",

pages = "778--797",

journal = "E M B O Journal",

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TY - JOUR

T1 - Compartment-specific aggregases direct distinct nuclear and cytoplasmic aggregate deposition

AU - Miller, Stephanie Bm

AU - Ho, Chi-Ting

AU - Winkler, Juliane

AU - Khokhrina, Maria

AU - Neuner, Annett

AU - Mohamed, Mohamed Yh

AU - Guilbride, D Lys

AU - Richter, Karsten

AU - Lisby, Michael

AU - Schiebel, Elmar

AU - Mogk, Axel

AU - Bukau, Bernd

PY - 2015/3/12

Y1 - 2015/3/12

N2 - Disruption of the functional protein balance in living cells activates protective quality control systems to repair damaged proteins or sequester potentially cytotoxic misfolded proteins into aggregates. The established model based on Saccharomyces cerevisiae indicates that aggregating proteins in the cytosol of eukaryotic cells partition between cytosolic juxtanuclear (JUNQ) and peripheral deposits. Substrate ubiquitination acts as the sorting principle determining JUNQ deposition and subsequent degradation. Here, we show that JUNQ unexpectedly resides inside the nucleus, defining a new intranuclear quality control compartment, INQ, for the deposition of both nuclear and cytosolic misfolded proteins, irrespective of ubiquitination. Deposition of misfolded cytosolic proteins at INQ involves chaperone-assisted nuclear import via nuclear pores. The compartment-specific aggregases, Btn2 (nuclear) and Hsp42 (cytosolic), direct protein deposition to nuclear INQ and cytosolic (CytoQ) sites, respectively. Intriguingly, Btn2 is transiently induced by both protein folding stress and DNA replication stress, with DNA surveillance proteins accumulating at INQ. Our data therefore reveal a bipartite, inter-compartmental protein quality control system linked to DNA surveillance via INQ and Btn2. Synopsis 'Juxtanuclear' deposits of misfolded protein in fact reside in a new intranuclear quality control compartment (INQ). INQ formation is dependent on Btn2, while cytosolic protein deposition is mediated by the Hsp42 aggregase. Proteotoxic stress in yeast results in organized sequestration of misfolded proteins at cytosolic CytoQ and nuclear INQ (former JUNQ) deposition sites. INQ deposition does not rely on substrate ubiquitination and does not target sequestered proteins for degradation. CytoQ and INQ formation relies on compartment-specific aggregases, the cytosolic Hsp42 and the nuclear Btn2. DNA replication stress triggers Btn2-dependent protein sequestration, linking cellular mechanisms coping with protein and DNA stress. 'Juxtanuclear' deposits of misfolded protein in fact reside in a new intranuclear quality control compartment (INQ). INQ formation is dependent on Btn2, while cytosolic protein deposition is mediated by the Hsp42 aggregase.

AB - Disruption of the functional protein balance in living cells activates protective quality control systems to repair damaged proteins or sequester potentially cytotoxic misfolded proteins into aggregates. The established model based on Saccharomyces cerevisiae indicates that aggregating proteins in the cytosol of eukaryotic cells partition between cytosolic juxtanuclear (JUNQ) and peripheral deposits. Substrate ubiquitination acts as the sorting principle determining JUNQ deposition and subsequent degradation. Here, we show that JUNQ unexpectedly resides inside the nucleus, defining a new intranuclear quality control compartment, INQ, for the deposition of both nuclear and cytosolic misfolded proteins, irrespective of ubiquitination. Deposition of misfolded cytosolic proteins at INQ involves chaperone-assisted nuclear import via nuclear pores. The compartment-specific aggregases, Btn2 (nuclear) and Hsp42 (cytosolic), direct protein deposition to nuclear INQ and cytosolic (CytoQ) sites, respectively. Intriguingly, Btn2 is transiently induced by both protein folding stress and DNA replication stress, with DNA surveillance proteins accumulating at INQ. Our data therefore reveal a bipartite, inter-compartmental protein quality control system linked to DNA surveillance via INQ and Btn2. Synopsis 'Juxtanuclear' deposits of misfolded protein in fact reside in a new intranuclear quality control compartment (INQ). INQ formation is dependent on Btn2, while cytosolic protein deposition is mediated by the Hsp42 aggregase. Proteotoxic stress in yeast results in organized sequestration of misfolded proteins at cytosolic CytoQ and nuclear INQ (former JUNQ) deposition sites. INQ deposition does not rely on substrate ubiquitination and does not target sequestered proteins for degradation. CytoQ and INQ formation relies on compartment-specific aggregases, the cytosolic Hsp42 and the nuclear Btn2. DNA replication stress triggers Btn2-dependent protein sequestration, linking cellular mechanisms coping with protein and DNA stress. 'Juxtanuclear' deposits of misfolded protein in fact reside in a new intranuclear quality control compartment (INQ). INQ formation is dependent on Btn2, while cytosolic protein deposition is mediated by the Hsp42 aggregase.

U2 - 10.15252/embj.201489524

DO - 10.15252/embj.201489524

M3 - Journal article

C2 - 25672362

SN - 0261-4189

VL - 34

SP - 778

EP - 797

JO - E M B O Journal

JF - E M B O Journal

IS - 6

ER -

Compartment-specific aggregases direct distinct nuclear and cytoplasmic aggregate deposition

Abstract

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