RIPosomes are targets of IRGM-SQSTM1-dependent autophagy

Area of Science:

• Immunology
• Cell Biology
• Microbiology

Background:

• The NOD1-NOD2-RIPK2-NFKB pathway is vital for immune responses to bacterial infections.
• Excessive NFKB signaling can disrupt innate immune balance.

Purpose of the Study:

• To investigate the role of autophagy in regulating the NOD1-NOD2-RIPK2-NFKB inflammatory axis.
• To understand how RIPK2 oligomers (RIPosomes) are degraded to control inflammation.

Main Methods:

• Studied RIPosome biogenesis and recruitment during bacterial infection.
• Investigated the degradation of RIPosomes via SQSTM1- and IRGM-dependent autophagy.
• Analyzed cytokine responses in IRGM-depleted cells and mice.
• Evaluated the effect of RIPK2 inhibition on gut inflammation in mice.

Main Results:

• Bacterial infection induces RIPosome formation to enhance NFKB-dependent inflammation.
• Selective autophagy degrades RIPosomes, limiting NOD1-NOD2-RIPK2-NFKB signaling.
• IRGM depletion leads to increased pro-inflammatory cytokine responses.
• Inhibition of RIPK2 reduces bacterial infection- and DSS-induced gut inflammation.

Conclusions:

• Autophagy selectively degrades RIPosomes to suppress inflammation.
• This mechanism is essential for maintaining innate immune homeostasis.