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EMBO J. 2015 Mar 12;34(6):778-97. doi: 10.15252/embj.201489524. Epub 2015 Feb 11.

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

Author information

1
Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) DKFZ-ZMBH Alliance, Heidelberg, Germany Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
2
Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) DKFZ-ZMBH Alliance, Heidelberg, Germany.
3
Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
4
Department of Biology, University of Copenhagen, Copenhagen N, Denmark.
5
Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) DKFZ-ZMBH Alliance, Heidelberg, Germany Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany a.mogk@zmbh.uni-heidelberg.de bukau@zmbh.uni-heidelberg.de.

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.

KEYWORDS:

chaperones; protein aggregation; protein disaggregation; proteostasis; ubiquitin–proteasome system

PMID:
25672362
PMCID:
PMC4369314
DOI:
10.15252/embj.201489524
[Indexed for MEDLINE]
Free PMC Article

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