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

Cell Rep. 2021 Jan 5;34(1):108599. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine / metabolism
  • Antigens, Neoplasm / metabolism*
  • Cell Line
  • Cell Survival
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Morphogenesis
  • Neurons / metabolism*
  • Nucleocytoplasmic Transport Proteins / metabolism*
  • Peptides / metabolism
  • Protein Biosynthesis
  • Proteolysis
  • RNA, Messenger / metabolism*
  • RNA-Binding Proteins / metabolism*
  • Ribosomes / metabolism*
  • Threonine / metabolism
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination


  • Antigens, Neoplasm
  • NEMF protein, human
  • Nucleocytoplasmic Transport Proteins
  • Peptides
  • RNA, Messenger
  • RNA-Binding Proteins
  • Threonine
  • LTN1 protein, human
  • Ubiquitin-Protein Ligases
  • Alanine