CARP-2 is an endosome-associated ubiquitin ligase for RIP and regulates TNF-induced NF-kappaB activation.
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.
Liao
Wentao
W
Laboratory of Immune Cell Biology, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Xiao
Qi
Q
Tchikov
Vladimir
V
Fujita
Ken-ichi
K
Yang
Wensheng
W
Wincovitch
Stephen
S
Garfield
Susan
S
Conze
Dietrich
D
El-Deiry
Wafik S
WS
Schütze
Stefan
S
Srinivasula
Srinivasa M
SM
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
D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D044767:Ubiquitin-Protein Ligases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases