CHMP2B regulates TDP-43 phosphorylation and cytotoxicity independent of autophagy via CK1

J Cell Biol. 2022 Jan 3;221(1):e202103033. doi: 10.1083/jcb.202103033. Epub 2021 Nov 2.

Abstract

The ESCRT protein CHMP2B and the RNA-binding protein TDP-43 are both associated with ALS and FTD. The pathogenicity of CHMP2B has mainly been considered a consequence of autophagy-endolysosomal dysfunction, whereas protein inclusions containing phosphorylated TDP-43 are a pathological hallmark of ALS and FTD. Intriguingly, TDP-43 pathology has not been associated with the FTD-causing CHMP2BIntron5 mutation. In this study, we identify CHMP2B as a modifier of TDP-43-mediated neurodegeneration in a Drosophila screen. Down-regulation of CHMP2B reduces TDP-43 phosphorylation and toxicity in flies and mammalian cells. Surprisingly, although CHMP2BIntron5 causes dramatic autophagy dysfunction, disturbance of autophagy does not alter TDP-43 phosphorylation levels. Instead, we find that inhibition of CK1, but not TTBK1/2 (all of which are kinases phosphorylating TDP-43), abolishes the modifying effect of CHMP2B on TDP-43 phosphorylation. Finally, we uncover that CHMP2B modulates CK1 protein levels by negatively regulating ubiquitination and the proteasome-mediated turnover of CK1. Together, our findings propose an autophagy-independent role and mechanism of CHMP2B in regulating CK1 abundance and TDP-43 phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy*
  • Casein Kinase I / metabolism*
  • Cell Death
  • Cell Line, Tumor
  • DNA-Binding Proteins / metabolism*
  • Disease Models, Animal
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / cytology*
  • Drosophila melanogaster / metabolism*
  • Neuroblastoma / pathology
  • Phosphorylation
  • Proteasome Endopeptidase Complex / metabolism
  • Ubiquitin / metabolism
  • Vesicular Transport Proteins / metabolism*

Substances

  • CHMP2B protein, Drosophila
  • DNA-Binding Proteins
  • Drosophila Proteins
  • TBPH protein, Drosophila
  • Ubiquitin
  • Vesicular Transport Proteins
  • Casein Kinase I
  • Proteasome Endopeptidase Complex