Selective autophagy of RIPosomes maintains innate immune homeostasis during bacterial infection

The NOD1/2-RIPK2 is a key cytosolic signaling complex that activates NF-kappa B pro-inflammatory response against invading pathogens. However, uncontrolled NF-kappa B signaling can cause tissue damage leading to chronic diseases. The mechanisms by which the NODs-RIPK2-NF-kappa B 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-kappa B 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-kappa B 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.

Automated summary

This study reveals a unique mechanism where bacterial infection induces the formation of endogenous RIPK2 oligomers (RIPosomes) that coat the bacteria to induce NF-kappa B response. Autophagy proteins IRGM and p62/SQSTM1 physically interact with NOD1/2, RIPK2 and RIPosomes to promote their selective autophagy and limit NF-kappa B activation. This study highlights the involvement of innate immune proteins and autophagy machinery in bacterial defense and immune homeostasis maintenance.