Induced TRIM21 ISGylation by IFN-β enhances p62 ubiquitination to prevent its autophagosome targeting

Cell Death Dis. 2021 Jul 13;12(7):697. doi: 10.1038/s41419-021-03989-x.

Abstract

The tripartite motif-containing protein 21 (TRIM21) plays important roles in autophagy and innate immunity. Here, we found that HECT and RLD domain containing E3 ubiquitin protein ligase 5 (HERC5), as an interferon-stimulated gene 15 (ISG15) E3 ligase, catalyzes the ISGylation of TRIM21 at the Lys260 and Lys279 residues. Moreover, IFN-β also induces TRIM21 ISGylation at multiple lysine residues, thereby enhancing its E3 ligase activity for K63-linkage-specific ubiquitination and resulting in increased levels of TRIM21 and p62 K63-linked ubiquitination. The K63-linked ubiquitination of p62 at Lys7 prevents its self-oligomerization and targeting to the autophagosome. Taken together, our study suggests that the ISGylation of TRIM21 plays a vital role in regulating self-oligomerization and localization of p62 in the autophagy induced by IFN-β.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Autophagosomes / drug effects
  • Autophagosomes / enzymology*
  • Autophagosomes / genetics
  • Autophagy
  • Cytokines / genetics
  • Cytokines / metabolism*
  • HEK293 Cells
  • Humans
  • Interferon-beta / pharmacology
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lysine
  • Protein Processing, Post-Translational* / drug effects
  • Ribonucleoproteins / genetics
  • Ribonucleoproteins / metabolism*
  • Sequestosome-1 Protein / genetics
  • Sequestosome-1 Protein / metabolism*
  • Ubiquitination
  • Ubiquitins / genetics
  • Ubiquitins / metabolism*

Substances

  • Cytokines
  • HERC5 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Ribonucleoproteins
  • SQSTM1 protein, human
  • SS-A antigen
  • Sequestosome-1 Protein
  • Ubiquitins
  • ISG15 protein, human
  • Interferon-beta
  • Lysine