title: cIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).
abstract: 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-κB 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-κB activation.
authors.affiliation: Department for Molecular Biomedical Research, VIB, Ghent, Belgium. mathieu.bertrand@dmbr.vib-ugent.be
authors.forename: Mathieu J M
authors.initials: MJ
authors.lastname: Bertrand
authors.forename: Saskia
authors.initials: S
authors.lastname: Lippens
authors.forename: An
authors.initials: A
authors.lastname: Staes
authors.forename: Barbara
authors.initials: B
authors.lastname: Gilbert
authors.forename: Ria
authors.initials: R
authors.lastname: Roelandt
authors.forename: Jelle
authors.initials: J
authors.lastname: De Medts
authors.forename: Kris
authors.initials: K
authors.lastname: Gevaert
authors.forename: Wim
authors.initials: W
authors.lastname: Declercq
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenabeele
mesh_terms: D000595:Amino Acid Sequence; D057809:HEK293 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D025801:Ubiquitin / Q000737:chemistry* / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: C119724:AGFG1 protein, human; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D028861:Nuclear Pore Complex Proteins; D016601:RNA-Binding Proteins; D025801:Ubiquitin; D051636:X-Linked Inhibitor of Apoptosis Protein; D044767:Ubiquitin-Protein Ligases; C506253:RIPK2 protein, human; C119705:RIPK3 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases