Format

Send to

Choose Destination
Mol Cell. 2018 Feb 15;69(4):551-565.e7. doi: 10.1016/j.molcel.2018.01.016.

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

Author information

1
Department of Early Discovery Biochemistry , Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
2
Department Biochemical and Cellular Pharmacology , Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
3
Department of Microchemistry, Proteomics and Lipidomics , Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
4
Department of Translational Immunology , Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
5
Department of Research Biology , Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
6
Department of Early Discovery Biochemistry , Genentech, 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: domagoj@gene.com.

Abstract

Inflammatory responses mediated by NOD2 rely on RIP2 kinase and ubiquitin ligase XIAP for the activation of nuclear factor κB (NF-κB), 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.

KEYWORDS:

IAP antagonist; NOD2; RIP2; RIPK2; XIAP; inflammatory signaling; kinase inhibitor; ubiquitin

PMID:
29452636
DOI:
10.1016/j.molcel.2018.01.016
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center