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

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.
Wentao Liao 1,  Qi Xiao,  Vladimir Tchikov,  Ken-ichi Fujita,  Wensheng Yang,  Stephen Wincovitch,  Susan Garfield,  Dietrich Conze,  Wafik S El-Deiry,  Stefan Schütze,  Srinivasa M Srinivasula
Affiliations

Affiliation

  • 1 Laboratory of Immune Cell Biology, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
PMID: 18450452 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.

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