Elucidating the novel mechanism of importins in NLRP6 inflammasome regulation

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Abstract Inflammasomes are multi-protein signaling scaffolds that form in the cytosol upon stimulation by pathogen and damage signals to activate caspase-1. Canonical inflammasome sensors are mainly nucleotide-binding domain (NBD) and leucine-rich repeat containing (NLR) proteins, such as NLRP1, NLRP3 and NLRP6. Once inflammasome is activated, caspase-1 is recruited to the platform and activated through proximity-induced autoproteolysis. Activated caspase-1 processes pro-interleukin (IL)-1b, pro-IL-18, and the pore-forming protein gasdermin D (GSDMD), resulting in the maturation and release of these cytokines, as well as pyroptotic cell death. NLRP6 plays versatile roles in host defense. It is highly expressed in the intestine and the liver. The inflammasome function of NLRP6 has been reported to protect the host from pathogen evasion and injury-induced tissue damage. On the other hand, the excessive NLRP6 inflammasome activation and the subsequent hyperactive IL-18 signaling may exacerbate the tissue damage and cause chronic inflammatory diseases such as inflammatory bowel disease (IBD). Whether there is an intrinsic cellular signal that tunes the activity of NLRP6 inflammasome becomes an intriguing question. The question is critical to understanding how our body maintains tissue homeostasis by harnessing this important inflammasome and to provide targeted therapy for certain diseases. Nuclear import is an essential cellular process in innate immune defense by translocating activated transcription factors into the nucleus for interferon production. Plant NLRs themselves have been reported to enable host defense through pathogen effector-mediated nuclear translocation. In our preliminary study, we found that importin-b1, a common nuclear import receptor, inhibits dsRNA-induced liquid-liquid phase separation of NLRP6 in-vitro, which implicates the potential link between nuclear import and NLRP6 inflammasome signaling. In this application, we will investigate the potential role of importins in regulating the NLRP6 inflammasome by tackling two questions: 1) molecular basis of the importin-NLRP6 interaction (cryo-electron microscopy and biochemistry), and 2) the roles of importin-b1 in negatively regulating NLRP6 inflammasome upon viral infection (inflammasome cell biology).