Mechanism, functions and conservation of SHRED, a novel pathway regulating protein quality control

• Applicant: Professor Dr. Sebastian Schuck
• Subject Area: Biochemistry
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 417974619

Proteins need to fold properly in order to fulfill their functions. Various stress conditions result in an accumulation of misfolded proteins, which pose a serious threat to normal cell function. Quality control mechanisms ensure that misfolded proteins are recognized and eliminated. Failure to clear misfolded proteins leads to disease, including neurodegenerative disorders.We have recently discovered a novel regulatory pathway in budding yeast that promotes efficient protein quality control by reprograming the substrate specificity of the ubiquitin ligase Ubr1. We have termed this pathway stress-induced homeostatically regulated protein degradation (SHRED). SHRED is activated when stress enhances transcription of the ROQ1 gene. The Roq1 protein is cleaved by the protease Ynm3, leading to exposure of a positively charged arginine residue at the new N-terminus of Roq1. By means of this arginine residue, cleaved Roq1 interacts with a substrate binding site in Ubr1 that normally recognizes substrates with positively charged N-terminal residues as part of the N-end rule pathway. Roq1-bound Ubr1 accelerates degradation of misfolded proteins by the proteasome and increases cellular resistance to protein misfolding. Furthermore, Ubr1 reprogramming by SHRED promotes the degradation of certain native, well-folded proteins, suggesting that SHRED has additional roles in proteome remodelling during physiological adaptation. These findings raise many new questions, including whether Roq1 acts as an allosteric regulator or as a substrate adaptor, which other cellular processes are influenced by SHRED and whether SHRED exists in higher eukaryotes.The goal of our proposed research is a comprehensive understanding of the mechanism, functions and evolutionary conservation of SHRED. Specifically, we aim to (1) elucidate the precise molecular mechanism of the pathway through in vitro reconstitution and structural studies, (2) gain a broad appreciation of the functions of SHRED in budding yeast, and (3) identify a putative SHRED pathway in mammals. These investigations promise general new insights into the regulation of ubiquitin ligases and quality control. Furthermore, they may ultimately enable pharmacological manipulation of protein quality control for therapeutic purposes.

• DFG Programme: Research Grants