# Caspase-1 Activation by the Inflammasomes

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2022 · $526,598

## Abstract

Inflammasomes are multi-protein complexes that assemble to activate caspase-1 in response to tissue damage
and infection by microbial or viral pathogens. Once activated, caspase-1 processes the inactive proforms of
interleukin-1β (IL-1β) and interleukin-18 (IL-18) to produce the active pro-inflammatory cytokines IL-1β and IL-
18, respectively. In addition, caspase-1 processes the gasdermin protein GSDMD to induce pyroptosis or
inflammatory cell death. The NLRP3 inflammasome is unique among the different inflammasomes in that it is
activated by diverse pathogen-associated and danger-associated molecular patterns (PAMPs and DAMPs)
derived from infection with microbial pathogens, or tissue damage. As a result, uncontrolled NLRP3 activation
can lead to a number of human inflammatory diseases, including gout, arthritis, atherosclerosis, and type 2
diabetes. The mechanism of NLRP3 activation by these seemingly unrelated stimuli is poorly understood but is
currently believed to require two distinct signals; a priming signal or “signal 1” produced by Toll-like receptors
(TLRs) and an activation signal or “signal 2” that induces fragmentation of trans Golgi network (TGN) and
binding to NEK7. Studies in the applicant's laboratory demonstrated that signal 1 induces post-translational
modification (PTM) of NLRP3 at critical sites via the MyD88 and TRIF signaling pathways and partial
oligomerization of NLRP3. In this application, studies are proposed to elucidate how TLR-induced PTM
contributes to posttranslational priming of the NLRP3 inflammasome by employing mass spectrometry to
identify and characterize all critical changes in the phosphorylation and other PTM profile of NLRP3 induced by
signal 1, and investigating how these changes contribute to activation of NLRP3. Additional aims will
investigate the effect of signal 1 and signal 1-induced PTM on NLRP3 association with dispersed TGN and
NEK7, and identify the TGN-associated kinases required for final assembly and activation of the
inflammasome. Finally, preliminary evidence suggest that kinases involved in the regulation of intracellular ion
homeostasis exert negative control on activation of NLRP3 by signal 2. Thus, additional experiments will
investigate how signaling from these kinases in macrophages impacts NEK7 phosphorylation and interaction
with NLRP3, and how genetic deficiency in these kinases impacts NLRP3-mediated pro-inflammatory responses
to PAMPs and DAMPs in vivo. Results from this research will provide fundamental new insights into the pathways
that regulate the assembly and activation of the NLRP3 inflammasome, and the cellular mechanisms that control
its activation. Successful completion of this study should have a high impact on the field by providing a unifying
paradigm for how NLRP3 can be regulated by an exceptionally diverse group of activating stimuli. Understanding
these mechanisms is of great scientific and health significance as this should better our understanding of the
mol...

## Key facts

- **NIH application ID:** 10401755
- **Project number:** 5R01AR078440-02
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Emad S Alnemri
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $526,598
- **Award type:** 5
- **Project period:** 2021-05-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10401755

## Citation

> US National Institutes of Health, RePORTER application 10401755, Caspase-1 Activation by the Inflammasomes (5R01AR078440-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10401755. Licensed CC0.

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