CARP-2 is an endosome-associated ubiquitin ligase for RIP and regulates TNF-induced NF-kappaB activation.
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Liao W, Xiao Q, Tchikov V, Fujita K, Yang W, Wincovitch S, Garfield S, Conze D, El-Deiry WS, Schutze S, Srinivasula SM
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.
- PubMed ID
- 18450452 [ View in PubMed]
- 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.