Immune regulator LGP2 targets Ubc13/UBE2N to mediate widespread interference with K63 polyubiquitination and NF-κB activation

Jessica J. Lenoir, Jean Patrick Parisien, Curt M. Horvath*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Lysine 63-linked polyubiquitin (K63-Ub) chains activate a range of cellular immune and inflammatory signaling pathways, including the mammalian antiviral response. Interferon and antiviral genes are triggered by TRAF family ubiquitin ligases that form K63-Ub chains. LGP2 is a feedback inhibitor of TRAF-mediated K63-Ub that can interfere with diverse immune signaling pathways. Our results demonstrate that LGP2 inhibits K63-Ub by association with and sequestration of the K63-Ub-conjugating enzyme, Ubc13/UBE2N. The LGP2 helicase subdomain, Hel2i, mediates protein interaction that engages and inhibits Ubc13/UBE2N, affecting control over a range of K63-Ub ligase proteins, including TRAF6, TRIM25, and RNF125, all of which are inactivated by LGP2. These findings establish a unifying mechanism for LGP2-mediated negative regulation that can modulate a variety of K63-Ub signaling pathways.

Original languageEnglish (US)
Article number110175
JournalCell reports
Volume37
Issue number13
DOIs
StatePublished - Dec 28 2021

Keywords

  • DHX58
  • IFN
  • K63-Ub
  • LGP2
  • RNF125
  • TRAF6
  • TRIM25
  • UBE2N
  • Ubc13

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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