Peli1 facilitates NLRP3 inflammasome activation by mediating ASC ubiquitination

Inflammasomes are crucial for innate immunity against infections and, when deregulated, also contribute to inflammatory diseases. Here, we identify a critical function of the E3 ubiquitin ligase Peli1 in regulating the activation of NLRP3 inflammasome. Peli1 deficiency impairs induction of interleukin-1 beta (IL-1 beta) secretion by different NLRP3 inducers, but not by inducers of the Aim2, NLRP1, and NLRC4 inflammasomes. Peli1-deficient mice have alleviated peritonitis induction by alum and display increased resistance to lipopolysaccharide (LPS) endotoxin shock, coupled with decreased serum concentration of IL-1 beta. Peli1 is required for NLRP3-induced caspase-1 activation and IL-1 beta maturation. Mechanistically, Peli1 conjugates K63 ubiquitin chain to lysine 55 of the inflammasome adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which in turn facilitates ASC/NLRP3 interaction and ASC oligomerization, thereby contributing to inflammasome activation. Peli1 deficiency impairs the ubiquitination of ASC and inhibits inflammasome activation. Our findings establish Peli1 as an important inflammasome regulator and suggest a mechanism by which Peli1 mediates inflammatory responses.

Automated summary

Inflammasomes are important for innate immunity against infections but can also contribute to inflammatory diseases when deregulated. Peli1, as an E3 ubiquitin ligase, plays a critical role in regulating the activation of NLRP3 inflammasome by promoting ASC ubiquitination and facilitating inflammasome assembly. Deficiency in Peli1 impairs NLRP3-induced caspase-1 activation and IL-1 beta maturation, highlighting its significance as an inflammasome regulator.