Selective autophagy of RIPosomes maintains innate immune homeostasis during bacterial infection

Subhash Mehto, Kautilya Kumar Jena, Rina Yadav, Swatismita Priyadarsini, Pallavi Samal, Sivaram Krishna, Kollori Dhar, Ashish Jain, Nishant Ranjan Chauhan, Krushna C. Murmu, Ramyasingh Bal, Rinku Sahu, Pundrik Jaiswal, Bhabani Sankar Sahoo, Srinivas Patnaik, Thomas A. Kufer, Tor Erik Rusten, Swati Chauhan, Punit Prasad, Santosh Chauhan

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

The NOD1/2-RIPK2 is a key cytosolic signaling complex that activates NF-κB pro-inflammatory response against invading pathogens. However, uncontrolled NF-κB signaling can cause tissue damage leading to chronic diseases. The mechanisms by which the NODs-RIPK2-NF-κB innate immune axis is activated and resolved remain poorly understood. Here, we demonstrate that bacterial infection induces the formation of endogenous RIPK2 oligomers (RIPosomes) that are self-assembling entities that coat the bacteria to induce NF-κB response. Next, we show that autophagy proteins IRGM and p62/SQSTM1 physically interact with NOD1/2, RIPK2 and RIPosomes to promote their selective autophagy and limit NF-κB activation. IRGM suppresses RIPK2-dependent pro-inflammatory programs induced by Shigella and Salmonella. Consistently, the therapeutic inhibition of RIPK2 ameliorates Shigella infection- and DSS-induced gut inflammation in Irgm1 KO mice. This study identifies a unique mechanism where the innate immune proteins and autophagy machinery are recruited together to the bacteria for defense as well as for maintaining immune homeostasis.

Original languageEnglish (US)
Article numbere111289
JournalEMBO Journal
Volume41
Issue number23
DOIs
StatePublished - Dec 1 2022
Externally publishedYes

Keywords

  • Irgm1
  • NOD1/2-RIPK2-NF-κB
  • RIPosomes
  • autophagy
  • inflammation

ASJC Scopus subject areas

  • General Neuroscience
  • Molecular Biology
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology

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