# Mechanisms of STING-associated autoinflammation

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $640,052

## Abstract

Project Abstract
The goal of this proposal is to define novel functions of STING in autoinflammation, cytokine secretion, and
immune dysregulation mediated by macrophages, innate lymphoid cells, and radioresistant cells. This work
builds on our prior discoveries using our model of STING-associated autoinflammation. The proposed studies
utilize several newly generated, already-validated model systems that will allow us to define cell type-specific
functions of STING in autoinflammatory disease pathogenesis.
STING gain-of-function mutations cause STING-associated vasculopathy with onset in infancy (SAVI), an
autoinflammatory disease characterized by T cell cytopenia, interstitial lung disease, Raynaud’s, skin lesions,
vasculopathy, and up-regulation of interferon (IFN)-stimulated genes. We previously generated a mouse model
of SAVI and discovered that the disease is mediated by type II IFN (IFN-γ) rather than type I or type III IFN. This
discovery was unexpected since type I IFN had been predicted to mediate disease. Additionally, we found that
innate lymphoid cell functions are altered in STING gain-of-function mice, and that macrophage activation
phenotypes and cytokine secretion are perturbed by constitutive STING signaling. We have previously
generated and published our floxed-STOP STING mutant mice, which permit cell type-specific expression of
STING. However, we have not yet studied cell type-specific functions of the type II IFN receptor and STING in
myeloid cells, innate lymphoid cells, and radioresistant cells in our model of STING-induced autoinflammation.
Therefore, we will define functions of the type II IFN receptor (Aim 1) and the effects of cell type-specific
expression of STING (Aim 2) in SAVI mice.
In unbiased, whole-genome CRISPR screening studies, we were led to the discovery that both WT STING and
STING gain-of-function can non-transcriptionally regulate pro-inflammatory cytokine secretion by altering the
post-Golgi endosomal pathways, and that this occurs without impacting secretion of other proteins. This function
of STING requires the protein ArfGAP2. Additionally, we found that ArfGAP2 deletion has no appreciable effect
on Golgi structure or on the transit of proteins from the ER to the Golgi when STING is inactive. However, when
STING is activated, cytokine trafficking and secretion is greatly diminished in the absence of ArfGAP2, and this
effect is non-transcriptional. We generated Arfgap2f/f mice crossed to transgenic Cre animals, and we found that
ArfGAP2 is deleted efficiently without impacting survival of target cells. In Aim 3, we will define the immunological
and physiological functions of ArfGAP2 in STING-mediated cytokine secretion and autoinflammation (Aim 3).

## Key facts

- **NIH application ID:** 10736474
- **Project number:** 2R01AI143982-07
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Jonathan J Miner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $640,052
- **Award type:** 2
- **Project period:** 2019-03-01 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10736474

## Citation

> US National Institutes of Health, RePORTER application 10736474, Mechanisms of STING-associated autoinflammation (2R01AI143982-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10736474. Licensed CC0.

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