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  • Selective autophagy of RIPosomes maintains innate immune homeostasis during bacterial infection.

Selective autophagy of RIPosomes maintains innate immune homeostasis during bacterial infection.

The EMBO journal (2022-10-13)
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
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.

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