{"doi":"10.1101/2025.06.30.662363","title":"Crosstalk Between ALPK1 and STING: A Synergistic Axis in Innate Immune Activation and Human Inflammatory Disease","abstract":"Alpha kinase 1 (ALPK1) is a cytosolic sensor of microbial sugar metabolites that activates NF-κB signaling through phosphorylation of the adaptor protein TIFA. Although canonically linked to NF-κB, 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 eIF2α, 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":569749,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9575,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":856244,"name":"Christina Torres Kozycki","orcid":"0000-0001-5405-4694","position":1,"is_corresponding":false},{"id":1475240,"name":"Ning-Na Huang","orcid":null,"position":2,"is_corresponding":false},{"id":1475241,"name":"Il-Young Hwang","orcid":null,"position":3,"is_corresponding":false},{"id":110325,"name":"Dima A. Hammoud","orcid":"0000-0001-7406-7871","position":4,"is_corresponding":false},{"id":218272,"name":"Daniel L. Kastner","orcid":"0000-0001-7188-4550","position":5,"is_corresponding":false},{"id":109652,"name":"John H. Kehrl","orcid":"0000-0002-6526-159X","position":6,"is_corresponding":false},{"id":299948,"name":"Chong-Shan Shi","orcid":null,"position":0,"is_corresponding":true}],"reference_count":33,"raw_metadata":null,"created_at":"2026-07-19T02:57:03.510013Z","pmid":"40631099","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}