IAPs Regulate Distinct Innate Immune Pathways to Co-ordinate the Response to Bacterial Peptidoglycans

Che A. Stafford, Kate E. Lawlor, Valentin J. Heim, Aleksandra Bankovacki, Jonathan P. Bernardini, John Silke, Ueli Nachbur

Research output: Contribution to journalArticleResearchpeer-review

13 Citations (Scopus)

Abstract

Inhibitors of apoptosis (IAPs) proteins are critical regulators of innate immune signaling pathways and therefore have potential as drug targets. X-linked IAP (XIAP) and cellular IAP1 and IAP2 (cIAP1 and cIAP2) are E3 ligases that have been shown to be required for signaling downstream of NOD2, an intracellular receptor for bacterial peptidoglycan. We used genetic and biochemical approaches to compare the responses of IAP-deficient mice and cells to NOD2 stimulation. In all cell types tested, XIAP is the only IAP required for signaling immediately downstream of NOD2, while cIAP1 and cIAP2 are dispensable for NOD2-induced nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) activation. However, mice lacking cIAP1 or TNFR1 have a blunted cytokine response to NOD2 stimulation. We conclude that cIAPs regulate NOD2-dependent autocrine TNF signaling in vivo and highlight the importance of physiological context in the interplay of innate immune signaling pathways. Stafford et al. show that XIAP is the only IAP required for the initial RIPK2/NOD2-dependent response to MDP, while autocrine TNF is required to amplify cytokine production in a cIAP1-dependent manner.

Original languageEnglish
Pages (from-to)1496-1508
Number of pages13
JournalCell Reports
Volume22
Issue number6
DOIs
Publication statusPublished - 6 Feb 2018
Externally publishedYes

Keywords

  • cell signaling
  • IAPs
  • inflammation
  • innate immunity
  • NOD2
  • RIPK2
  • ubiquitin

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