TY - JOUR
T1 - Failure to Degrade CAT-Tailed Proteins Disrupts Neuronal Morphogenesis and Cell Survival
AU - Udagawa, Tsuyoshi
AU - Seki, Moeka
AU - Okuyama, Taku
AU - Adachi, Shungo
AU - Natsume, Tohru
AU - Noguchi, Takuya
AU - Matsuzawa, Atsushi
AU - Inada, Toshifumi
N1 - Funding Information:
We thank S. Hoshino for providing β-globin nonstop reporter constructs. This work was supported by AMED (grant JP 19gm1110010 to T.I.), MEXT/JSPS KAKENHI (grants JP18H03977 and JP 19H05281 to T.I. and grants JP16K07243 and JP20K06615 and T.U.), research grants from the Takeda Science Foundation (T.I. and T.U.) and the Uehara Memorial Foundation (T.I.), the Mochida Memorial Foundation for Medical and Pharmaceutical Research (T.U.), and the Suzuken Memorial Foundation (T.U.).
Publisher Copyright:
© 2020 The Author(s)
PY - 2021/1/5
Y1 - 2021/1/5
N2 - 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. 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.
AB - 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. 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.
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U2 - 10.1016/j.celrep.2020.108599
DO - 10.1016/j.celrep.2020.108599
M3 - Article
C2 - 33406423
AN - SCOPUS:85099604171
VL - 34
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 1
M1 - 108599
ER -