期刊
CURRENT BIOLOGY
卷 18, 期 9, 页码 641-649出版社
CELL PRESS
DOI: 10.1016/j.cub.2008.04.017
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资金
- Intramural NIH HHS [Z01 BC010629-04, Z99 CA999999] Funding Source: Medline
- NCI NIH HHS [R01 CA097100, CA 97100] Funding Source: Medline
Background: The proinflarnmatory 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-kappa B, and failure to downregulate TNF-induced NF-kappa B 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-kappa B 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-kappa B. Conclusions: CARP-2 acts at the level of endocytic vesicles to limit the intensity of TNF-induced NF-kappa B activation by the regulated elimination of a necessary signaling component within the receptor complex.
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