CARP-2 is an endosome-associated ubiquitin ligase for RIP and regulates TNF-induced NF-kappaB activation

Curr Biol. 2008 May 6;18(9):641-9. doi: 10.1016/j.cub.2008.04.017.

Abstract

Background: The proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) elicits cellular responses by signaling through a receptor complex that includes the essential adaptor molecule RIP. One important consequence of signaling is activation of the transcription factor NF-kappaB, and failure to downregulate TNF-induced NF-kappaB transcriptional activity results in chronic inflammation and death. Internalization of the receptor complex plays an important regulatory role in TNF signaling.

Results: We report that CARP-2, a RING domain-containing ubiquitin protein ligase (E3), is a negative regulator of TNF-induced NF-kappaB activation. By virtue of its phospholipid-binding FYVE domain, CARP-2 localized to endocytic vesicles, where it interacted with internalized TNF-receptor complex, resulting in RIP ubiquitination and degradation. Knockdown of CARP-2 stabilized TNFR1-associated polyubiquitinated RIP levels after TNF simulation and enhanced activation of NF-kappaB.

Conclusions: CARP-2 acts at the level of endocytic vesicles to limit the intensity of TNF-induced NF-kappaB activation by the regulated elimination of a necessary signaling component within the receptor complex.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Endocytosis / physiology
  • Humans
  • NF-kappa B / metabolism*
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Transport Vesicles / enzymology*
  • Tumor Necrosis Factor-alpha / metabolism*
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Ubiquitin-Protein Ligases
  • Receptor-Interacting Protein Serine-Threonine Kinases