Biology subjects

Szaflarski, W.

Publications and source records attributed to Szaflarski, W..

3 recordsLinked to original sources

bioRxiv2025

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. 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

cell biology↗

bioRxiv2021

Mechanisms of translation inhibition and suppression of Stress Granule formation by cisplatin

Platinum-based antineoplastic drugs, such as cisplatin, are commonly used to induce tumor cell death. Cisplatin is believed to induce apoptosis as a result of cisplatin-DNA adducts that inhibit DNA and RNA synthesis. Although idea that DNA damage underlines anti-proliferative effects of cisplatin is dominant in cancer research, there is a poor correlation between the degree of the cell sensitivity to cisplatin and the extent of DNA platination. Here, we propose a novel mechanism of cisplatin-mediated cytotoxicity. We show that cisplatin suppresses formation of Stress Granules (SGs), pro-survival RNA granules with multiple roles in cellular metabolism. Mechanistically, cisplatin inhibits cellular translation to promote disassembly of polysomes and aggregation of ribosomal subunits. As SGs are in equilibrium with polysomes, cisplatin-induced shift towards ribosomal aggregation suppresses SG formation and promotes cellular death. Our data also explain nephrotoxic, neurotoxic and ototoxic effects of cisplatin treatment.

cell biology↗

bioRxiv2020

A Novel Stress Response Pathway Regulates Ribosome Biogenesis

Production of ribosomes is an energy-intensive process owing to the intricacy of these massive macromolecular machines. Each human ribosome contains 80 ribosomal proteins and four non-coding RNAs. Accurate assembly requires precise regulation of protein and RNA subunits. In response to stress, the integrated stress response (ISR) rapidly inhibits global translation. How rRNA is coordinately regulated with the rapid inhibition of ribosomal protein synthesis is not known. Here we show that stress specifically inhibits the first step of rRNA processing. Unprocessed rRNA is stored within the nucleolus, and, when stress resolves, it re-enters the ribosome biogenesis pathway. Retention of unprocessed rRNA within the nucleolus aids in the maintenance of this organelle. This response is independent of the ISR or inhibition of cellular translation but represents an independent stress-response pathway that we term Ribosome Biogenesis Stress Response (RiBiSR). Failure to coordinately regulate ribosomal protein translation and rRNA production results in nucleolar fragmentation. Our study unveils a novel stress response pathway that aims at conserving energy, preserving the nucleolus, and prevents further stress by regulation of rRNA processing.

biochemistry↗