# Bacterial activation and evasion of a PP2A phosphatase – Pyrin - Gasdermin D axis

> **NIH NIH R21** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $209,375

## Abstract

Abstract:
Many successful Gram-negative pathogens evade or thwart innate immunity via Type III secretion systems
(T3SS), often essential for virulence. Yersinia bacteria cause infections such as gastroenteritis and plague, and
is an excellent model system for studies of T3SS effects on innate immune responses. Triggering of
inflammasome complexes typically culminate with activation of caspase-1 that then cleaves and matures pro-
forms of inflammatory cytokines IL-1b and IL-18, cytokines with well-known antibacterial effects, and the pore-
forming and pyroptosis-inducing protein Gasdermin D (GSDMD) at residue D276. GSDMD pores also allow
passing of IL-1b/IL-18, but the role of GSDMD cleavage in the resistance to many bacterial infections is poorly
understood. We have uncovered an extraordinarily complex set of manipulations of inflammasomes by the
Yersinia T3SS. One caspase-1 activation pathway is triggered by Yersinia effector YopE, a RhoA inhibitor, and
leads to substantial IL-1b/IL-18 release in myeloid cells via Pyrin inflammasomes. Many details of Pyrin
activation remain unclear, but Pyrin does not appear to be directly triggered by toxins or effectors such as YopE
or Clostridium TcdB, rather by pathological disturbance of host RhoA signaling. Spontaneously activating alleles
of Pyrin are also linked to auto-inflammatory diseases such as familial Mediterranean fever.
It is believed that inactive Pyrin is phosphorylated, and an unknown phosphatase is needed to trigger Pyrin
inflammasomes. Our experiments suggest PP2A phosphatase is involved. We hypothesize that PP2A
phosphatase positively regulates bacterial toxin-induced Pyrin activation leading to cleavage of
caspase-1, IL-1b and GSDMD. Furthermore, effective inhibitory mechanisms such as those promoted by
Yersinia T3SS effector YopM can block this effective anti-bacterial pathway to promote infection. YopM
appears to specifically inhibit the T3SS induced Pyrin inflammasome, likely by interactions with several
kinases. Our results suggest that attenuated Yersinia strains lacking YopM regain virulence in the absence of
Pyrin or GSDMD. Our goal is to decipher the protective mechanisms against infection mediated by PP2A,
Pyrin, caspase-1 and GSDMD but suppressed by YopM, in vitro and in vivo. Our work will bridge the gap of
knowledge by clarifying key questions related to how Pyrin is regulated by phosphatases and kinases.

## Key facts

- **NIH application ID:** 10364690
- **Project number:** 5R21AI159706-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Egil Lien
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $209,375
- **Award type:** 5
- **Project period:** 2021-03-05 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10364690

## Citation

> US National Institutes of Health, RePORTER application 10364690, Bacterial activation and evasion of a PP2A phosphatase – Pyrin - Gasdermin D axis (5R21AI159706-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10364690. Licensed CC0.

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