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.
authors: Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) DKFZ-ZMBH Alliance, Heidelberg, Germany Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
authors: Stephanie B M
authors: SB
authors: Miller
authors: Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) DKFZ-ZMBH Alliance, Heidelberg, Germany Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
authors: Chi-Ting
authors: CT
authors: Ho
authors: Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) DKFZ-ZMBH Alliance, Heidelberg, Germany Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
authors: Juliane
authors: J
authors: Winkler
authors: Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) DKFZ-ZMBH Alliance, Heidelberg, Germany Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
authors: Maria
authors: M
authors: Khokhrina
authors: Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) DKFZ-ZMBH Alliance, Heidelberg, Germany.
authors: Annett
authors: A
authors: Neuner
authors: Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) DKFZ-ZMBH Alliance, Heidelberg, Germany Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
authors: Mohamed Y H
authors: MY
authors: Mohamed
authors: Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) DKFZ-ZMBH Alliance, Heidelberg, Germany.
authors: D Lys
authors: DL
authors: Guilbride
authors: Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
authors: Karsten
authors: K
authors: Richter
authors: Department of Biology, University of Copenhagen, Copenhagen N, Denmark.
authors: Michael
authors: M
authors: Lisby
authors: Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) DKFZ-ZMBH Alliance, Heidelberg, Germany.
authors: Elmar
authors: E
authors: Schiebel
authors: 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.
authors: Axel
authors: A
authors: Mogk
authors: 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.
authors: Bernd
authors: B
authors: Bukau
mesh_terms: D026905:Amino Acid Transport Systems / Q000378:metabolism / Q000502:physiology*; D015153:Blotting, Western; D002451:Cell Compartmentation / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism*; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008856:Microscopy, Fluorescence; D016253:Microscopy, Immunoelectron; D008954:Models, Biological; D066329:Protein Aggregates / Q000502:physiology*; D017510:Protein Folding; D012441:Saccharomyces cerevisiae / Q000378:metabolism / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism / Q000502:physiology*; D059008:Time-Lapse Imaging; D054875:Ubiquitination; D033921:Vesicular Transport Proteins; D050888:Heat-Shock Proteins, Small
chemical_list: D026905:Amino Acid Transport Systems; D006360:Heat-Shock Proteins; D066329:Protein Aggregates; D029701:Saccharomyces cerevisiae Proteins; C473804:BTN2 protein, S cerevisiae; D033921:Vesicular Transport Proteins; D050888:Heat-Shock Proteins, Small; C098005:HSP42 protein, S cerevisiae
keywords: chaperones; protein aggregation; protein disaggregation; proteostasis; ubiquitin–proteasome system