Cell Rep. 2024 Feb 26. pii: S2211-1247(24)00188-8. [Epub ahead of print]43(3): 113860
Liang Lv,
Jinyou Mo,
Yumin Qing,
Shuchao Wang,
Leijie Chen,
Anna Mei,
Ru Xu,
Hualin Huang,
Jieqiong Tan,
Yifu Li,
Jia Liu.
The ribosome-associated protein quality control (RQC) pathway acts as a translational surveillance mechanism to maintain proteostasis. In mammalian cells, the cytoplasmic RQC pathway involves nuclear export mediator factor (NEMF)-dependent recruitment of the E3 ligase Listerin to ubiquitinate ribosome-stalled nascent polypeptides on the lysine residue for degradation. However, the quality control of ribosome-stalled nuclear-encoded mitochondrial nascent polypeptides remains elusive, as these peptides can be partially imported into mitochondria through translocons, restricting accessibility to the lysine by Listerin. Here, we identify a Listerin-independent organelle-specific mitochondrial RQC pathway that acts on NEMF-mediated carboxy-terminal poly-alanine modification. In the pathway, mitochondrial proteins carrying C-end poly-Ala tails are recognized by the cytosolic E3 ligase Pirh2 and the ClpXP protease in the mitochondria, which coordinately clear ribosome-stalled mitochondrial nascent polypeptides. Defects in this elimination pathway result in NEMF-mediated aggregates and mitochondrial integrity failure, thus providing a potential molecular mechanism of the RQC pathway in mitochondrial-associated human diseases.
Keywords: CP: Microbiology; CP: Molecular biology; ClpXP; Listerin; NEMF; Pirh2; mitochondrion