PLoS One. 2011;6(9):e22356. Epub 2011 Sep 12.

cIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).External

Bertrand, M. J., Lippens, S., Staes, A., Gilbert, B., Roelandt, R., De Medts, J., Gevaert, K., Declercq, W., Vandenabeele, P.,
--- - Department for Molecular Biomedical Research, VIB, Ghent, Belgium. mathieu.bertrand@dmbr.vib-ugent.be
The RIP kinases have emerged as essential mediators of cellular stress that integrate both extracellular stimuli emanating from various cell-surface receptors and signals coming from intracellular pattern recognition receptors. The molecular mechanisms regulating the ability of the RIP proteins to transduce the stress signals remain poorly understood, but seem to rely only partially on their kinase activities. Recent studies on RIP1 and RIP2 have highlighted the importance of ubiquitination as a key process regulating their capacity to activate downstream signaling pathways. In this study, we found that XIAP, cIAP1 and cIAP2 not only directly bind to RIP1 and RIP2 but also to RIP3 and RIP4. We show that cIAP1 and cIAP2 are direct E3 ubiquitin ligases for all four RIP proteins and that cIAP1 is capable of conjugating the RIPs with diverse types of ubiquitin chains, including linear chains. Consistently, we show that repressing cIAP1/2 levels affects the activation of NF-kappaB that is dependent on RIP1, -2, -3 and -4. Finally, we identified Lys51 and Lys145 of RIP4 as two critical residues for cIAP1-mediated ubiquitination and NF-kappaB activation.
PMID: 21931591External
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
In vitro interaction
  DD1 DD2 Reference
Family DD1 DD2 Method Species Region Expression Species Region Expression
CARD CIAP1 Link RIPK2 GST fusion protein pull-down Not specified Not specified E.coli Human Not specified In vitro translation 21931591
CARD CIAP2 Link RIPK2 GST fusion protein pull-down Not specified Not specified E.coli Human Not specified In vitro translation 21931591
(Link: click this icon to show interactions only between the two corresponding DDs)
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
In vivo interaction
  Endogenous
expression
Overexpression DD1 DD2 Reference
Family DD1 DD2 Method Species Region Species Region
CARD CIAP1 Link RIPK2 Co-immunoprecipitation HEK239 Not specified Not specified Human Not specified 21931591
CARD CIAP2 Link RIPK2 Co-immunoprecipitation HEK239 Not specified Not specified Human Not specified 21931591
(Link: click this icon to show interactions only between the two corresponding DDs)