Regulation of cell type-specific sting signaling

The National Institute of Allergy and Infectious Diseases (NIAID) awarded $902,741 to the University of Washington on July 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855).

The award funds basic research into the cell type-specific regulation of STING signaling, a central pathway in innate immune response with implications for antiviral immunity, antitumor immunity, and aging-associated inflammation. The research investigates why STING activation produces distinct outcomes across cell types: in macrophages, STING triggers type I interferon production and cell survival, whereas in hematopoietic progenitor cells, it induces rapid cell death without interferon production. The investigator team has employed paired genome-wide CRISPR screens to identify unique regulatory mechanisms governing these divergent responses and has identified MBNL1 (muscleblind-like 1), an mRNA splicing regulatory factor, as essential for STING-activated cell death in progenitor cells. The research connects these findings to myotonic dystrophy type 1 (DM1), a multi-system muscular dystrophy affecting over 4 million people worldwide, exploring potential links between STING pathway dysfunction and DM1 pathogenesis. Additional investigation focuses on ANKFY1, a membrane trafficking protein identified as a negative regulator of the pathway.

The University of Washington Office of Sponsored Programs administers the award. Work is performed in Seattle, Washington. The period of performance runs from July 1, 2026, through June 30, 2031.

Abstract

The cgas-sting DNA sensing pathway has emerged as a key innate immune response that is important for antiviral immunity, mediates antitumor immunity, and contributes to autoimmune and aging-associated diseases. Sting activation results in the production of type i interferons (ifns), proinflammatory cytokines, autophagy, and cell death. Current models envision that all four of these outcomes can be activated within the same cell, with the primacy of a particular outcome determined by currently unknown means. We have discovered that distinct signaling outputs of sting signaling are instead cell type-specific: macrophages produce ifns and survive after sting activation, whereas hematopoietic progenitor cells do not produce ifns and instead undergo rapid cell death. We performed paired genome-wide crispr screens and identified unique regulation of cell death in progenitor cells and IFN production in macrophages. We have found that intrinsic (mitochondrial) apoptosis is the principal mechanism of cell death in progenitor cells, and we identified the mrna splicing regulatory factor muscleblind-like 1 (MBNL1) as a specific and essential factor required for sting-activated cell death. Rare mutations in the human MBNL1 gene itself or a more commonly found CTG repeat expansion within an intron of the dmpk gene that sequesters MBNL1 from its intended mrna targets cause myotonic dystrophy type 1 (DM1), which is the most common form of muscular dystrophy that affects over 4 million people worldwide. DM1 manifests as a multi-system disease characterized by cardiac, respiratory, ocular, and neurological defects, many of which resemble premature or accelerated aging. However, nothing is known about a potential connection to sting, which also controls age-related inflammation and cellular senescence. Moreover, we have identified the membrane trafficking protein ANKFY1 as a novel and potent negative regulator of sting-activated IFN production in macrophages, and we have discovered that ANKFY1 is essential for sting-mediated autophagy. Our central hypothesis is that that cell type-specific sting signaling is controlled by distinct regulatory programs and contributes to the outcomes of sting activation in vivo. To explore this hypothesis, we will perform a series of refined crispr screens to further define how sting activates cell death in progenitor cells and ifns in macrophages. We will define the functions of MBNL1 and ANKFY1 in regulation of discrete outputs of sting signaling. The scientific premise of this grant is that definition of cell type-specific sting signaling outcomes will provide a foundational framework and a roadmap for new therapies targeted to specific facets of sting activation.