title: CARP-2 is an endosome-associated ubiquitin ligase for RIP and regulates TNF-induced NF-kappaB activation.
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.
authors.affiliation: Laboratory of Immune Cell Biology, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Wentao
authors.initials: W
authors.lastname: Liao
authors.forename: Qi
authors.initials: Q
authors.lastname: Xiao
authors.forename: Vladimir
authors.initials: V
authors.lastname: Tchikov
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Fujita
authors.forename: Wensheng
authors.initials: W
authors.lastname: Yang
authors.forename: Stephen
authors.initials: S
authors.lastname: Wincovitch
authors.forename: Susan
authors.initials: S
authors.lastname: Garfield
authors.forename: Dietrich
authors.initials: D
authors.lastname: Conze
authors.forename: Wafik S
authors.initials: WS
authors.lastname: El-Deiry
authors.forename: Stefan
authors.initials: S
authors.lastname: Schütze
authors.forename: Srinivasa M
authors.initials: SM
authors.lastname: Srinivasula
mesh_terms: D002460:Cell Line; D004705:Endocytosis / Q000502:physiology; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D022161:Transport Vesicles / Q000201:enzymology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D044767:Ubiquitin-Protein Ligases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases