# Elucidating the novel mechanism of importins in NLRP6 inflammasome regulation

> **NIH NIH R21** · WASHINGTON UNIVERSITY · 2024 · $194,375

## Abstract

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).

## Key facts

- **NIH application ID:** 10904635
- **Project number:** 5R21AI173896-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Chen Shen
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $194,375
- **Award type:** 5
- **Project period:** 2023-08-10 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10904635

## Citation

> US National Institutes of Health, RePORTER application 10904635, Elucidating the novel mechanism of importins in NLRP6 inflammasome regulation (5R21AI173896-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10904635. Licensed CC0.

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