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

Abstract

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. HighlightsO_LICHIP remodels the nucleolus into a reversible protein quality control (PQC) compartment during heat stress C_LIO_LIVCP drives flux of ubiquitinated substrates and prevents premature resumption of rRNA synthesis C_LIO_LINOL6 promotes, while WDR55 restricts, nucleolar storage of misfolded proteins C_LIO_LIDistinct nucleolar morphologies (free-flow, peripheral, sealed) encode PQC states C_LIO_LIUbiquitination and deubiquitination act as switchable signals, not passive damage marks C_LIO_LINucleolar PQC is integrated with ISR, ER stress, and stress granule pathways C_LI