| First Author | Liao W | Year | 2008 |
| Journal | Curr Biol | Volume | 18 |
| Issue | 9 | Pages | 641-9 |
| PubMed ID | 18450452 | Mgi Jnum | J:148683 |
| Mgi Id | MGI:3846069 | Doi | 10.1016/j.cub.2008.04.017 |
| Citation | Liao W, et al. (2008) CARP-2 is an endosome-associated ubiquitin ligase for RIP and regulates TNF-induced NF-kappaB activation. Curr Biol 18(9):641-9 |
| abstractText | 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. |
