Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 281, Issue 19, Pages 13636-13643Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M600620200
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- NIAID NIH HHS [AI058048] Funding Source: Medline
- NIGMS NIH HHS [GM065899] Funding Source: Medline
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Stimulation of cells with tumor necrosis factor (TNF alpha) triggers a recruitment of various signaling molecules, such as RIP, to the TNF alpha receptor 1 complex, leading to activation of NF-K B. Previous studies indicate that RIP plays an essential role for TNF alpha- induced NF-KB activation, but the molecular mechanism by which RIP mediates TNF alpha signals to activate NF-KB is not fully defined. Earlier studies suggest that RIP undergoes a ligand- dependent ubiquitination. However, it remains to be determined whether the ubiquitination of RIP is required for TNF alpha-induced NF-KB activation. In this study, we have identified Lys(377) of RIP as the functional ubiquitination site, because mutating this residue to arginine completely abolished RIP-mediated NF-K B activation. The K377R mutation of RIP cannot undergo ligand-dependent ubiquitination and fails to recruit its downstream signaling components into the TNF alpha receptor 1 complex. Together, our studies provide the first genetic evidence that the ubiquitination of RIP is required for TNF alpha-induced NF-KB activation.
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