Failure to Degrade CAT-Tailed Proteins Disrupts Neuronal Morphogenesis and Cell Survival

• Published in: Cell reports (Cambridge) 2021-01, Vol.34 (1), p.108599, Article 108599
• Main Authors: Udagawa, Tsuyoshi, Seki, Moeka, Okuyama, Taku, Adachi, Shungo, Natsume, Tohru, Noguchi, Takuya, Matsuzawa, Atsushi, Inada, Toshifumi
• Format: Article
• Language: English
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108599

Ribosome-associated quality control (RQC) relieves stalled ribosomes and eliminates potentially toxic nascent polypeptide chains (NCs) that can cause neurodegeneration. During RQC, RQC2 modifies NCs with a C-terminal alanine and threonine (CAT) tail. CAT tailing promotes ubiquitination of NCs for proteasomal degradation, while RQC failure in budding yeast disrupts proteostasis via CAT-tailed NC aggregation. However, the CAT tail and its cytotoxicity in mammals have remained largely uncharacterized. We demonstrate that NEMF, a mammalian RQC2 homolog, modifies translation products of nonstop mRNAs, major erroneous mRNAs in mammals, with a C-terminal tail mainly composed of alanine with several other amino acids. Overproduction of nonstop mRNAs induces NC aggregation and caspase-3-dependent apoptosis and impairs neuronal morphogenesis, which are ameliorated by NEMF depletion. Moreover, we found that homopolymeric alanine tailing at least partially accounts for CAT-tail cytotoxicity. These findings explain the cytotoxicity of CAT-tailed NCs and demonstrate physiological significance of RQC on proper neuronal morphogenesis and cell survival. [Display omitted] •NEMF mediates CAT tailing of nonstop proteins targeted for degradation by LTN1•Mammalian CAT tails are mainly composed of alanine, with several other amino acids•Nonstop protein overproduction induces protein aggregation and apoptosis•NEMF depletion ameliorates neurite morphology defects by LTN1 depletion Udagawa et al. report that NEMF modifies the C-terminal end of nonstop proteins with CAT tails composed of alanine and several other amino acids and that nonstop protein overproduction induces protein aggregation and apoptosis and impairs neuronal morphogenesis, which are partially ameliorated by NEMF depletion, thus demonstrating CAT-tail cytotoxicity in mammalian cells.