# Human NLRP11 function in non-canonical inflammasome activation by bacterial pathogen LPS

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $530,908

## Abstract

The gram-negative bacterial outer membrane glycolipid lipopolysaccharide (LPS) is recognized by both
the cell surface TLR4 complex and cytosolic sensors. Recognition of bacterial LPS in the cytosol induces the
activation of the caspase-4/caspase-5 (CASP4/5, human) or CASP11 (mouse) inflammasome, signaling
platforms that trigger pyroptotic cell death. The dogma for recognition of bacterial LPS, based on the simplest
interpretation of non-physiological data showing that CASP4/11 bind bacterial LPS in vitro, is that cytosolic
bacterial LPS is directly sensed by CASP4/11 rather than by a pattern recognition receptor. We recently found
that NLRP11, a poorly characterized primate-specific member of a family of pattern recognition receptors, is a
pattern recognition receptor for cytosolic bacterial LPS.
 We found that efficient cell death induced by cytosolic bacterial LPS in human macrophages depends on
NLRP11 function in the CASP4 inflammasome pathway. We initially identified NLRP11 in a genome-wide
screen of human myeloid-derived cells for factors that promote cell death during infection with the gram-
negative bacterial pathogen Shigella flexneri. We propose to leverage our findings to uncover mechanisms of
NLRP11 function in cytosolic bacterial LPS-triggered activation of the human CASP4 inflammasome, including
the role of variants of S. flexneri LPS in this process.
1. Define determinants of host-pathogen interaction of NLRP11 with bacterial LPS and caspase(s)
and of NLRP11 specificity for caspase(s). We will define the molecular domains and sequences that
mediate bacterial LPS interaction with NLRP11 and NLRP11 with CASP4.
2. Determine mechanisms of host NLRP11-mediated activation of CASP4 in response to cytosolic
bacterial pathogens and cytosolic bacterial LPS. We will test our hypothesis that resting state NLRP11 is
autoinhibited and activated NLRP11 triggers CASP4 activation by proximity-induced dimerization and will test
the requirements for bacterial LPS in NLRP11 activation.
3. Test whether host NLRP11 recognition is modulated by specific LPS modifications or modes of
LPS delivery by gram-negative bacterial pathogens. We will determine the role of selected modifications of
LPS from S. flexneri on its recognition by NLRP11 and on NLRP11-dependent CASP4 activation and will test
our hypothesis that NLRP11 is most critical to CASP4 responses when S. flexneri LPS is in micelle-reducing
conditions.
 Our focus is to determine mechanisms of cytosolic bacterial LPS-triggered NLRP11-mediated activation of
the human CASP4 inflammasome. We are uniquely positioned to accomplish these goals. Our insights are
likely to have broad implications for gram-negative pathogenesis and thus be of great interest to the
pathogenesis community.

## Key facts

- **NIH application ID:** 10802428
- **Project number:** 5R01AI173030-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Marcia B Goldberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $530,908
- **Award type:** 5
- **Project period:** 2023-03-06 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10802428

## Citation

> US National Institutes of Health, RePORTER application 10802428, Human NLRP11 function in non-canonical inflammasome activation by bacterial pathogen LPS (5R01AI173030-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10802428. Licensed CC0.

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