NEMF-mediated Listerin-independent mitochondrial translational surveillance by E3 ligase Pirh2 and mitochondrial protease ClpXP

• DOI: 10.1016/j.celrep.2024.113860
• Publication Date: 2024-02-26T17:32:50Z
• Authors: Liang Lv; Jinyou Mo; Yumin Qing; Shuchao Wang; Leijie Chen; Anna Mei; Ru Xu; Hualin Huang; Jieqiong Tan; Yifu Li; Jia Liu
• Keywords: Mammals; QH301-705.5; Ubiquitin-Protein Ligases; Lysine; CP: Microbiology; Ubiquitination; ClpXP; Mitochondria; NEMF; Listerin; Protein Biosynthesis; Endopeptidases; mitochondrion; NEMF; Listerin; Pirh2; ClpXP; Animals; Humans; mitochondrion; CP: Molecular biology; Biology (General); Peptides; Pirh2; Peptide Hydrolases

The ribosome-associated protein quality control (RQC) pathway acts as a translational surveillance mechanism to maintain proteostasis. In mammalian cells, the cytoplasmic RQC involves nuclear export mediator factor (NEMF)-dependent recruitment of E3 ligase Listerin ubiquitinate ribosome-stalled nascent polypeptides on lysine residue for degradation. However, nuclear-encoded mitochondrial remains elusive, these peptides can be partially imported into mitochondria through translocons, restricting accessibility by Listerin. Here, we identify Listerin-independent organelle-specific that NEMF-mediated carboxy-terminal poly-alanine modification. pathway, proteins carrying C-end poly-Ala tails are recognized cytosolic Pirh2 and ClpXP protease in mitochondria, which coordinately clear polypeptides. Defects this elimination result aggregates integrity failure, thus providing potential molecular mitochondrial-associated human diseases.