# Structural and mechanistic elucidation of non-canonical inflammasome signaling

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2022 · $410,000

## Abstract

Project Summary/Abstract
Caspase-4/-5/-11 non-canonical inflammasomes have been known to play pivotal roles in various inflammatory
and infectious diseases, such as sepsis. Current studies demonstrate that caspase-4/-5/-11 are activated by
directly sensing intracellular microbial infections, such as lipopolysaccharide (LPS, also known as endotoxin), or
endogenous products, such as oxidized phospholipids (e.g., OxPAPC), through their N-terminal caspase
activation and recruitment domains (CARDs) and C-terminal catalytic domains, respectively. However, the
molecular mechanisms of how caspase-4/-5/-11 recognize their ligands and how caspase-4/-5/-11 are activated
upon binding ligands remain unknown. In this proposal, we aim to elucidate the structural basis of non-canonical
inflammasome signaling by characterizing the interactions between caspase-4/-5/-11 and ligands - LPS and
OxPAPC, and determining the high-resolution structures of caspase/-4/-5/-11 in complex with ligands. Our
structural findings will provide new therapeutic strategies for sepsis and other non-canonical inflammasome-
associated diseases. We propose three specific aims to achieve our goal: 1) Biochemical characterization of the
interactions between caspase-4/-5/-11 and LPS-including the identification of the essential structural elements
in the LPS molecule and key residues on caspase-4/-5/-11 CARDs that are required for caspase-4/-5/-11
activation; 2) Determine high-resolution structures of caspase-4/-5/-11 CARDs both in their inactive form and in
complex with LPS; 3) Characterize the interactions between caspase-4/-11 and OxPAPC, and determine the
high resolution structures of caspase-4/-11 catalytic domains in complex with OxPAPC. We will pursue these
aims using cutting-edge experimental approaches including biochemical and biophysical characterization, X-ray
crystallography, mass spectrometry, electron microscopy, and cellular experiments. The proposed studies will
significantly expand our current knowledge on the mechanisms of non-canonical inflammasome signaling, and
provide rationale and a structural basis for designing novel strategies to control the activation of the non-
canonical inflammasome for better treatment of related diseases.

## Key facts

- **NIH application ID:** 10374131
- **Project number:** 5R01AI158435-02
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Jianbin Ruan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $410,000
- **Award type:** 5
- **Project period:** 2021-03-17 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10374131

## Citation

> US National Institutes of Health, RePORTER application 10374131, Structural and mechanistic elucidation of non-canonical inflammasome signaling (5R01AI158435-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10374131. Licensed CC0.

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