# Molecular Mechanism of NLRP1 and CARD8 Inflammasome Regulation by DPP9

> **NIH NIH F31** · HARVARD MEDICAL SCHOOL · 2021 · $32,867

## Abstract

Abstract
The inflammatory response provides an absolutely essential host defense mechanism that, if perturbed, can
itself cause a large number of human diseases. Collectively, innate immune responses integrate a number of
genome-encoded sensor proteins to combat threats such as pathogens and endogenous damage. Selected
throughout multicellular evolution, these proteins recognize patterns of pathogen-specific molecules, such as
bacterial flagellin and lipopolysaccharide, with remarkable sensitivity and selectivity. Following detection, host
cells launch coordinated defensive measures through innate immune signaling pathways. In one such pathway,
cytosolic sensor proteins assemble supramolecular signaling complexes called canonical inflammasomes to
active the zymogen pro-caspase-1. Subsequent downstream signaling leads to cytokine release and pyroptosis,
an inflammatory form of cell death consisting of cell lysis, alerting phagocytic cells to the site of infection or
damage. While imperative to the inflammatory response, aberrant gain-of-function mutations in sensor proteins
can cause constitutive pyroptosis that leads to human diseases such as inflammatory bowel disease,
cardiovascular disease, gout, and other rare autoinflammatory disorders. Moreover, inhibiting the inflammasome
pathway is a therapeutic strategy for preventing lethal septic shock. Despite its therapeutic potential, many
mechanistic details underlying the activation of inflammasomes remain unknown. Herein, I propose to elucidate
the molecular mechanisms underlying the activation and regulation of two inflammasome sensor proteins,
NLRP1 and CARD8, by the prolyl peptidase DPP9. DPP9 directly binds both NLRP1 and CARD8, and
pharmacological inhibition of DPP9 results in either NLRP1 or CARD8 activation dependent on cell type. DPP9,
however, may not act on NLRP1 or CARD8 as substrate; therefore, the mechanism by which DPP9 mediates
NLRP1 and CARD8 inhibition remains poorly understood, but might involve scaffolding a repressive complex
and/or its catalytic activity. I aim to interrogate this system through a combination of structural, biochemical, and
cellular approaches. Completion of these independent aims will significantly advance our understanding of innate
immunity and expedite treatments that improve human health.

## Key facts

- **NIH application ID:** 10134733
- **Project number:** 1F31AI152267-01A1
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Louis Robert Hollingsworth
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $32,867
- **Award type:** 1
- **Project period:** 2021-02-01 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134733

## Citation

> US National Institutes of Health, RePORTER application 10134733, Molecular Mechanism of NLRP1 and CARD8 Inflammasome Regulation by DPP9 (1F31AI152267-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10134733. Licensed CC0.

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