Disruption of XIAP-RIP2 Association Blocks NOD2-Mediated Inflammatory Signaling

被引:92
作者
Goncharov, Tatiana [1 ]
Hedayati, Stefanie [1 ]
Mulvihill, Melinda M. [2 ]
Izrael-Tomasevic, Anita [3 ]
Zobel, Kerry [1 ]
Jeet, Surinder [4 ]
Fedorova, Anna V. [1 ]
Eidenschenk, Celine [2 ]
deVoss, Jason [4 ,6 ]
Yu, Kebing [3 ]
Shaw, Andrey S. [5 ]
Kirkpatrick, Donald S. [3 ]
Fairbrother, Wayne J. [1 ]
Deshayes, Kurt [1 ]
Vucic, Domagoj [1 ]
机构
[1] Genentech Inc, Dept Early Discovery Biochem, 1 DNA Way, San Francisco, CA 94080 USA
[2] Genentech Inc, Dept Biochem & Cellular Pharmacol, 1 DNA Way, San Francisco, CA 94080 USA
[3] Genentech Inc, Dept Microchem Prote & Lipid, 1 DNA Way, San Francisco, CA 94080 USA
[4] Genentech Inc, Dept Translat Immunol, 1 DNA Way, San Francisco, CA 94080 USA
[5] Genentech Inc, Depr Res Biol, 1 DNA Way, San Francisco, CA 94080 USA
[6] Amgen Inc, San Francisco, CA 94080 USA
关键词
ALPHA-DEPENDENT APOPTOSIS; KAPPA-B ACTIVATION; NOD-LIKE RECEPTORS; CELL-DEATH; IAP ANTAGONISTS; INNATE IMMUNITY; KINASE-ACTIVITY; CROHNS-DISEASE; BOWEL-DISEASE; HOST-DEFENSE;
D O I
10.1016/j.molcel.2018.01.016
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Inflammatory responses mediated by NOD2 rely on RIP2 kinase and ubiquitin ligase XIAP for the activation of nuclear factor kappa B (NF-kappa B), mitogen-activated protein kinases (MAPKs), and cytokine production. Herein, we demonstrate that selective XIAP antagonism blocks NOD2-mediated inflammatory signaling and cytokine production by interfering with XIAP-RIP2 binding, which removes XIAP from its ubiquitination substrate RIP2. We also establish that the kinase activity of RIP2 is dispensable for NOD2 signaling. Rather, the conformation of the RIP2 kinase domain functions to regulate binding to the XIAP-BIR2 domain. Effective RIP2 kinase inhibitors block NOD2 signaling by disrupting RIP2-XIAP interaction. Finally, we identify NOD2 signaling and XIAP-dependent ubiquitination sites on RIP2 and show that mutating these lysine residues adversely affects NOD2 pathway signaling. Overall, these results reveal a critical role for the XIAP-RIP2 interaction in NOD2 inflammatory signaling and provide a molecular basis for the design of innovative therapeutic strategies based on XIAP antagonists and RIP2 kinase inhibitors.
引用
收藏
页码:551 / +
页数:22
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