biostudies-literatureMehto SEuropean Molecular Biology OrganizationDepartment of Science and Technology, Ministry of Science and Technology, IndiaDBT/Wellcome Trust India AllianceWellcome TrustDepartment of Biotechnology, Ministry of Science and Technology, Indiae111289https://www.ebi.ac.uk/biostudies/studies/S-EPMC9713718biostudies-literatureUnknown41(23)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.The EMBO journalSelective autophagy of RIPosomes maintains innate immune homeostasis during bacterial infection.PMC9713718DST/INSPIRE/04/2019/001857BT/PR45223/MED/29/1613/2022IA/I/15/2/502071Chauhan SSamal PSahu RKufer TAPrasad PPatnaik SDhar KBal RJaiswal PRusten TESahoo BSJena KKJain AKrishna SMehto SPriyadarsini SMurmu KCChauhan NRYadav RfalseSelective autophagy of RIPosomes maintains innate immune homeostasis during bacterial infection.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.2022-01-01T00:00:00Z2022 Dec2026-06-21T03:20:55.931Z2025-02-19T03:56:07.337ZS-EPMC97137183622190210.15252/embj.2022111289