Shigella hijacks the glomulin–cIAPs–inflammasome axis to promote inflammation

Authors:
Publisher website
Google Scholar
Abstract
Shigella deploys a unique mechanism to manipulate macrophage pyroptosis by delivering the IpaH7.8 E3 ubiquitin ligase via its type III secretion system. IpaH7.8 ubiquitinates glomulin (GLMN) and elicits its degradation, thereby inducing inflammasome activation and pyroptotic cell death of macrophages. Here, we show that GLMN specifically binds cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1 and cIAP2), members of the inhibitor of apoptosis (IAP) family of RING‐E3 ligases, which results in reduced E3 ligase activity, and consequently inflammasome‐mediated death of macrophages. Importantly, reducing the levels of GLMN in macrophages via IpaH7.8, or siRNA‐mediated knockdown, enhances inflammasome activation in response to infection by Shigella, Salmonella, or Pseudomonas, stimulation with NLRP3 inflammasome activators (including SiO2, alum, or MSU), or stimulation of the AIM2 inflammasome by poly dA:dT. GLMN binds specifically to the RING domain of both cIAPs, which inhibits their self‐ubiquitination activity. These findings suggest that GLMN is a negative regulator of cIAP‐mediated inflammasome activation, and highlight a unique Shigella stratagem to kill macrophages, promoting severe inflammation. Synopsis Inflammasomes induce caspase‐1 activation, cytokine production and macrophage pyroptosis upon bacterial infection. GLMN, an inhibitor of RING‐type E3 ligases, targeted by the Shigella effector IpaH7.8, negatively regulates inflammasomes by interfering with cIAP E3 ligase activities. cIAP1 and cIAP2 E3 ligases, but not XIAP, promote NLR inflammasome activation. Glomulin (GLMN) interacts with cIAP1 and cIAP2 to inhibit self‐ubiquitination of both cIAPs. Shigella IpaH7.8 ubiquitinates GLMN, promoting its degradation and inflammasome activation. A serine residue in the cIAP RING domain is critical for GLMN interaction, and inflammasome activation.
Funding Information
  • a Grant‐in‐Aid for Specially Promoted Research (23000012)
  • a Grant‐in‐Aid for Scientific Research (16K08772)
  • a Grant‐in‐Aid for Young Scientists (19790315)
  • the Research Grant of Takeda Science Foundation
  • Kato Memorial Bioscience Foundation
  • University of Tokyo
  • Astellas Foundation for Research on Metabolic Disorders
  • the Uehara Memorial Foundation Research Fellowship
  • the JSPS Excellent Young Researchers Overseas Visit Program (21・10053)
  • The Japan Initiative for Global Research Network on Infectious Diseases
  • Grants from the Yakult Central Institute

This publication has 41 references indexed in Scilit: