Compartment‐specific aggregases direct distinct nuclear and cytoplasmic aggregate deposition

<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>Saccharomyces cerevisiae</jats:italic> indicates that aggregating proteins in the cytosol of eukaryotic cells partition between cytosolic juxtanuclear (<jats:styled-content style="fixed-case">JUNQ</jats:styled-content>) and peripheral deposits. Substrate ubiquitination acts as the sorting principle determining <jats:styled-content style="fixed-case">JUNQ</jats:styled-content> deposition and subsequent degradation. Here, we show that <jats:styled-content style="fixed-case">JUNQ</jats:styled-content> unexpectedly resides inside the nucleus, defining a new intranuclear quality control compartment, <jats:styled-content style="fixed-case">INQ</jats:styled-content>, for the deposition of both nuclear and cytosolic misfolded proteins, irrespective of ubiquitination. Deposition of misfolded cytosolic proteins at <jats:styled-content style="fixed-case">INQ</jats:styled-content> involves chaperone‐assisted nuclear import via nuclear pores. The compartment‐specific aggregases, Btn2 (nuclear) and Hsp42 (cytosolic), direct protein deposition to nuclear <jats:styled-content style="fixed-case">INQ</jats:styled-content> and cytosolic (CytoQ) sites, respectively. Intriguingly, Btn2 is transiently induced by both protein folding stress and <jats:styled-content style="fixed-case">DNA</jats:styled-content> replication stress, with <jats:styled-content style="fixed-case">DNA</jats:styled-content> surveillance proteins accumulating at <jats:styled-content style="fixed-case">INQ</jats:styled-content>. Our data therefore reveal a bipartite, inter‐compartmental protein quality control system linked to <jats:styled-content style="fixed-case">DNA</jats:styled-content> surveillance via <jats:styled-content style="fixed-case">INQ</jats:styled-content> and Btn2.</jats:p>