Crosstalk Between ALPK1 and STING: A Synergistic Axis in Innate Immune Activation and Human Inflammatory Disease
Shi, C.-S.; Kozycki, C.; Huang, N.-N.; Hwang, I.-Y.; Hammoud, D. A.; Kastner, D. L.; Kehrl, J. H.
Show abstract
Alpha kinase 1 (ALPK1) is a cytosolic sensor of microbial sugar metabolites that activates NF-{kappa}B signaling through phosphorylation of the adaptor protein TIFA. Although canonically linked to NF-{kappa}B, individuals with gain-of-function ALPK1 mutations also show features of interferon-driven inflammation. Here, we show that ALPK1 activation enhances multiple outputs of the stimulator of interferon genes (STING) pathway, including both canonical and noncanonical responses such as STING proton channel-dependent LC3B lipidation and NLRP3 inflammasome activation. Furthermore, ALPK1 signaling activates eIF2, an effector of the integrated stress response. Conversely, STING activation increases ALPK1 protein expression and triggers TIFA-Threonine 9 phosphorylation. Clinically, individuals with ALPK1-mediated disease exhibit premature intracranial mineralization and elevated cerebrospinal fluid neopterin, both associated with dysregulated interferon signaling. These findings support a model of bidirectional signaling between ALPK1 and STING, in which microbial and nucleic acid sensing pathways can amplify one another. This crosstalk provides a mechanistic framework for understanding innate immune signaling relevant to both homeostasis and disease.
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