CHIP, VCP, and Nucleolar Gatekeepers Remodel the Nucleolus into a Stress-Responsive Proteostasis Hub

The nucleolus, classically dedicated to ribosome biogenesis, also acts as a stress-responsive proteostasis hub. During heat shock, misfolded proteins accumulate in its granular component (GC), but whether this is passive or regulated has been unclear. We show that the ubiquitin ligase CHIP remodels the nucleolus into a reversible protein quality control (PQC) compartment by diverting HSP70 from refolding toward sequestration and transiently suppressing rRNA synthesis. This process requires the segregase VCP, which mediates ubiquitinated substrate flux and couples nucleolar PQC with nuclear and ER stress responses. Functional genomics identify NOL6 and WDR55 as intrinsic gatekeepers with opposing effects on sequestration. We further define three structural states - free-flow, peripheral, and sealed - that encode PQC capacity and recovery potential. Thus, nucleolar proteostasis is revealed as an actively regulated continuum, linking chaperones, ubiquitination, and ribosome biogenesis with global stress adaptation.