# Two novel threonine phosphorylations of STAT2 impact inflammatory responses to bacterial infection.

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $562,646

## Abstract

Project Summary
The major transcription factor that drives responses to type I interferon (IFN-I) is ISGF3, comprised of tyrosine-
phosphorylated STATs 1 and 2 and the DNA binding protein IRF9. The threonine phosphorylation of STAT2 on T387
and T404 profoundly affects the ability of IFN-I to drive gene expression and dependent biological functions.
Furthermore, STAT2 lacking tyrosine phosphorylation (U-STAT2) enhances the expression of NF-κB target genes
that encode several chemokines and pro-inflammatory cytokines (for example, IL-6), and also inhibits the ability of
IFN-γ to activate the tyrosine phosphorylation of STAT1 and downstream gene expression. These non-canonical
functions of U-STAT2 are also regulated by its phosphorylation on T387 and T404. Dramatic effects are seen with
mice carrying homozygous T-A mutations at each of these two sites. The defective response to IFN-I in T403A mice
causes them to be highly susceptible to infections with vesicular stomatitis virus (VSV) or Herpes Simplex virus (HSV).
(The numbers for mice are T386 and T403.) The responses of T403A mice to inflammatory stimuli are also greatly
compromised. Ulcerative colitis is a chronic disease in which the lining of the colon becomes inflamed and develops
ulcers. In the dextran sulfate sodium (DSS)-induced model of ulcerative colitis, T403A/T403A knockin mice, in which
this site cannot be phosphorylated, are very much more sensitive than WT/WT mice to DSS-induced mortality and
weight loss. Sepsis and septic shock are the leading causes of death in non-coronary intensive care units. We have
shown that the immune response in sepsis transitions from an early/hyper-inflammatory to a late/hypo-inflammatory,
immunosuppressive phenotype that is associated with multiple organ dysfunction involving lung, heart, kidney and
liver. Furthermore, prolonged hypo-inflammation is associated with impaired pathogen clearance. Compared with wild-
type controls, T403A/T403A mice are protected from, and T386A/T386A mice are sensitized to challenge with
lipopolysaccharide (LPS), an inducer of septic shock, and the induction of IFN-I and IL-6 expression is suppressed in
T403A/T403A mice. Our primary objectives follow. 1) We want to understand in detail how the phosphorylation
of STAT2 on these two threonine residues is regulated (which activating signals? which kinases? which
phosphatases?). 2) We want to understand in detail how pro-inflammatory mechanisms are affected by STAT2
threonine phosphorylation. 3) We want to use this information to develop novel therapeutic approaches to
inflammatory responses to commensal bacteria, especially colonic inflammation and septic shock. We
anticipate that we can parlay improved understanding of the roles of threonine phosphorylation of STAT2 in
inflammation and infection into novel therapeutic approaches, and that the discovery of novel approaches to
ameliorate bacterially-induced acute inflammation may also be helpful in other inflammatory conditions...

## Key facts

- **NIH application ID:** 10026693
- **Project number:** 1R01AI153085-01
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** GEORGE ROBERT STARK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $562,646
- **Award type:** 1
- **Project period:** 2020-08-07 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10026693

## Citation

> US National Institutes of Health, RePORTER application 10026693, Two novel threonine phosphorylations of STAT2 impact inflammatory responses to bacterial infection. (1R01AI153085-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10026693. Licensed CC0.

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