# Mechanistic Investigation of the Role of FBXW7 in Inflammasome Activation

> **NIH NIH R21** · SCRIPPS RESEARCH INSTITUTE, THE · 2024 · $276,000

## Abstract

The NLRP3 inflammasome is a key regulator of inflammatory responses. These include responses to
infection by pathogens but also are a component of many chronic inflammatory diseases, including
neurodegenerative diseases. The end point of the inflammasome response is the secretion of mature
inflammatory cytokines, IL-1β and IL-18. To accomplish this, the NLRP3 inflammasome is assembled and
activated through a complex series of events, some of which remain poorly understood. The first step in
NLRP3 inflammasome activation is the de novo biosynthesis of NLRP3 itself through transcriptional
upregulation, and the assembly or newly synthesized NLRP3 molecules into inactive oligomers. How this
occurs is only partially understood. We have evidence that the ubiquitin ligase SCFFBXW7 is required for this
particular process. The objective of the proposed research is to test a hypothesis where SCFFBXW7 places
ubiquitin chains on the N-terminal end of NLRP3 which are bound and capped by a UIM (ubiquitin interacting
motif) near the C-terminus. The constraints enforced by this interaction would lock NLRP3 in a conformation
that would promote the assembly of inactive oligomers.

## Key facts

- **NIH application ID:** 10983619
- **Project number:** 1R21AI182967-01A1
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Steven I Reed
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $276,000
- **Award type:** 1
- **Project period:** 2024-06-17 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10983619

## Citation

> US National Institutes of Health, RePORTER application 10983619, Mechanistic Investigation of the Role of FBXW7 in Inflammasome Activation (1R21AI182967-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10983619. Licensed CC0.

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