# Function of the Sts protein phosphodiesterase domain

> **NIH NIH R21** · UNIVERSITY OF MINNESOTA · 2022 · $195,700

## Abstract

PROJECT SUMMARY
The Sts proteins (Sts-1 and -2) negatively regulate signaling pathways within cells of the mammalian immune
system. Mice lacking Sts expression (Sts-/-) are profoundly resistant to infection by clinically relevant fungal and
bacterial pathogens, including Candida albicans, Francisella tularensis, and Staphylococcus aureus. Resistance
is associated with rapid pathogen clearance and reduced inflammation. We recently identified a novel,
functionally relevant, phosphodiesterase (PDE) enzyme activity of Sts-1. We hypothesize that this
unprecedented activity plays a key role in regulating immune cell signaling pathways. To fulfill our long-term goal
of developing novel therapies for infectious diseases, the objective of this proposal is to elucidate the signaling
role of the Sts-1 PDE domain and identify molecular determinants of its function. Guided by strong preliminary
data, we will test our hypothesis and accomplish our overall objective by pursuing the following two specific aims:
1) Elucidate the role of the Sts PDE domain in negatively regulating immune cell signaling pathways; and
2) Identify the substrate, and define the molecular determinants of function of the Sts PDE domain.
In the first aim, we will utilize cell- and animal-based models to evaluate Sts-1 PDE domain function. In the
second aim, we will use both a targeted, kinetics-based approach and global metabolomics to define Sts-1 PDE
domain substrate breadth and specificity. In addition, we will determine the mechanism and molecular features
that define the enzyme’s function. The proposed studies are innovative because they focus on a newly
discovered enzyme domain that has previously not been characterized. The proposed research is significant
because it is expected to substantially expand our understanding of the role of the Sts proteins in regulating
immune cell responses. As therapeutic down-modulation of Sts function is expected to increase resistance to
select microbial pathogens, we aim to exploit the results of these studies to develop new anti-microbial therapies
that target the Sts-1 PDE domain.

## Key facts

- **NIH application ID:** 10407644
- **Project number:** 5R21AI156238-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Jarrod B French
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $195,700
- **Award type:** 5
- **Project period:** 2021-05-19 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10407644

## Citation

> US National Institutes of Health, RePORTER application 10407644, Function of the Sts protein phosphodiesterase domain (5R21AI156238-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10407644. Licensed CC0.

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