Journal
CELL REPORTS
Volume 34, Issue 1, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.108599
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Funding
- AMED [JP 19gm1110010]
- MEXT/JSPS KAKENHI [JP18H03977, JP 19H05281, JP16K07243, JP20K06615]
- Takeda Science Foundation
- Uehara Memorial Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Suzuken Memorial Foundation
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Ribosome-associated quality control modifies nascent polypeptide chains, promoting their degradation, which is essential for proper neuronal morphogenesis and cell survival. However, the mechanism and cytotoxicity of the C-terminal CAT tail in mammals remain unclear.
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.
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