Delayed protein translocation protects mitochondria against toxic CAT-tailed proteins

Bertram, Nils; Izawa, Toshiaki; Thoma, Felix; Schwenkert, Serena ; Duvezin-Caubet, Stéphane; Park, Sae-Hun; Wagener, Nikola; Devin, Anne; Osman, Christof; Neupert, Walter und Mokranjac, Dejana (2025): Delayed protein translocation protects mitochondria against toxic CAT-tailed proteins. In: Molecular Cell, Bd. 85, Nr. 21: S. 4082-4092

Abstract

Ribosome-associated protein quality control (RQC) protects cells against the toxic effects of faulty polypeptides produced by stalled ribosomes. However, mitochondria are vulnerable to C-terminal alanyl and threonyl (CAT)-tailed proteins that are generated in this process, and faulty nuclear-encoded mitochondrial proteins are handled by the recently discovered mitoRQC. Here, we performed a genome-wide screen in yeast to identify additional proteins involved in mitoRQC. We found that peptidyl-tRNA hydrolase 2 (Pth2), present in the mitochondrial outer membrane, influences aggregation of CAT-tailed proteins without majorly affecting the CAT-tailing process itself. Peptidyl-tRNA hydrolase activity is essential during this process, yet the activity of Pth2 can be substituted by another peptidyl-tRNA hydrolase upon proper localization. Our data suggest that Pth2 acts by modulating protein translocation and that the mitochondrial proteostasis network is relieved through increased access of CAT-tailed proteins to cytosolic chaperones. Other hits obtained in the screen show that, in general, delayed protein translocation protects mitochondria against toxic CAT-tailed proteins.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Biologie
• Themengebiete: 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften; Biologie
• ISSN: 10972765
• Sprache: Englisch