{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T20:30:46Z","timestamp":1783542646932,"version":"3.55.0"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2025,2,1]],"date-time":"2025-02-01T00:00:00Z","timestamp":1738368000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute on Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["RF1AG066578"],"award-info":[{"award-number":["RF1AG066578"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000065","name":"National Institute on Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["RF1AG056320"],"award-info":[{"award-number":["RF1AG056320"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000065","name":"National Institute on Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["RF1AG065342"],"award-info":[{"award-number":["RF1AG065342"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000957","name":"Alzheimer\u2019s Association","doi-asserted-by":"crossref","award":["AARG-22-923849"],"award-info":[{"award-number":["AARG-22-923849"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Mitochondrial antiviral-signaling protein (MAVS) is a key adapter protein required for inducing type I interferons (IFN-Is) and other antiviral effector molecules. The formation of MAVS aggregates on mitochondria is essential for its activation; however, the regulatory mitochondrial factor that mediates the aggregation process is unknown. Our recent work has identified the protein Aggregatin as a critical seeding factor for \u03b2-amyloid peptide aggregation. Here we show that Aggregatin serves as a cross-seed for MAVS aggregates on mitochondria to orchestrate innate immune signaling. Aggregatin is primarily localized to mitochondria in the cytosol and has the ability to induce MAVS aggregation and MAVS-dependent IFN-I responses alone in both HEK293 cells and human leukemia monocytic THP-1 cells. Mitochondrial Aggregatin level increases upon viral infection. Also, Aggregatin knockout suppresses viral infection-induced MAVS aggregation and IFN-I signal cascade activation. Nemo-like kinase is further identified as a kinase phosphorylating Aggregatin at Ser59 to regulate its stability and cross-seeding activity. Collectively, our finding reveals an important physiological function of Aggregatin in innate immunity by cross-seeding MAVS aggregation.<\/jats:p>","DOI":"10.1093\/jimmun\/vkae019","type":"journal-article","created":{"date-parts":[[2025,2,18]],"date-time":"2025-02-18T20:15:01Z","timestamp":1739909701000},"page":"238-252","source":"Crossref","is-referenced-by-count":4,"title":["Aggregatin is a mitochondrial regulator of MAVS activation to drive innate immunity"],"prefix":"10.1093","volume":"214","author":[{"given":"Ju","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Arizona , Tucson, AZ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mao","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Arizona , Tucson, AZ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanbin","family":"Xiyang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Arizona , Tucson, AZ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyue","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Arizona , Tucson, AZ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devanshi","family":"Shukla","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Arizona , Tucson, AZ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawei","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Arizona , Tucson, AZ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4325-1216","authenticated-orcid":false,"given":"Masaru","family":"Miyagi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Case Western Reserve University , Cleveland, OH,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8511-7141","authenticated-orcid":false,"given":"Hisashi","family":"Fujioka","sequence":"additional","affiliation":[{"name":"Electron Microscopy Core Facility, Case Western Reserve University , Cleveland, OH,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona , Tucson, AZ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8657-0159","authenticated-orcid":false,"given":"Xinglong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Arizona , Tucson, AZ,","place":["United States"]},{"name":"Department of Pathology, Case Western Reserve University , Cleveland, OH,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,2,18]]},"reference":[{"key":"2025030420232804600_vkae019-B1","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1056\/NEJM200008033430506","article-title":"Innate immunity","volume":"343","author":"Medzhitov","year":"2000","journal-title":"N Engl J Med"},{"key":"2025030420232804600_vkae019-B2","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1038\/nri3787","article-title":"Type I interferons in infectious disease","volume":"15","author":"McNab","year":"2015","journal-title":"Nat Rev Immunol"},{"key":"2025030420232804600_vkae019-B3","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1038\/nri3133","article-title":"Immunomodulatory functions of type I interferons","volume":"12","author":"Gonzalez-Navajas","year":"2012","journal-title":"Nat Rev Immunol"},{"key":"2025030420232804600_vkae019-B4","doi-asserted-by":"crossref","first-page":"7285","DOI":"10.1074\/jbc.R116.774562","article-title":"The molecular basis for differential type I interferon signaling","volume":"292","author":"Schreiber","year":"2017","journal-title":"J Biol Chem"},{"key":"2025030420232804600_vkae019-B5","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1172\/JCI133737","article-title":"Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease","volume":"130","author":"Roy","year":"2020","journal-title":"J Clin Invest"},{"key":"2025030420232804600_vkae019-B6","doi-asserted-by":"crossref","first-page":"744348","DOI":"10.3389\/fmicb.2021.744348","article-title":"MAVS: a two-sided CARD mediating antiviral innate immune signaling and regulating immune homeostasis","volume":"12","author":"Chen","year":"2021","journal-title":"Front Microbiol"},{"key":"2025030420232804600_vkae019-B7","doi-asserted-by":"crossref","first-page":"e1003537","DOI":"10.1371\/journal.ppat.1003537","article-title":"Cross-seeding of misfolded proteins: implications for etiology and pathogenesis of protein misfolding diseases","volume":"9","author":"Morales","year":"2013","journal-title":"PLoS Pathog"},{"key":"2025030420232804600_vkae019-B8","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol"},{"key":"2025030420232804600_vkae019-B9","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025030420232804600_vkae019-B10","doi-asserted-by":"crossref","DOI":"10.1083\/jcb.202101019","article-title":"Translational regulation in the brain by TDP-43 phase separation","volume":"220","author":"Gao","year":"2021","journal-title":"J Cell Biol"},{"key":"2025030420232804600_vkae019-B11","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1038\/nprot.2013.143","article-title":"Genome engineering using the CRISPR-Cas9 system","volume":"8","author":"Ran","year":"2013","journal-title":"Nat Protoc"},{"key":"2025030420232804600_vkae019-B12","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1002\/ar.21486","article-title":"Decreased cytochrome c oxidase subunit VIIa in aged rat heart mitochondria: immunocytochemistry","volume":"294","author":"Fujioka","year":"2011","journal-title":"Anat Rec (Hoboken)"},{"key":"2025030420232804600_vkae019-B13","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1002\/ar.22523","article-title":"Mitochondrial division in rat cardiomyocytes: an electron microscope study","volume":"295","author":"Fujioka","year":"2012","journal-title":"Anat Rec (Hoboken)"},{"key":"2025030420232804600_vkae019-B14","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/s41467-019-13962-0","article-title":"FAM222A encodes a protein which accumulates in plaques in Alzheimer's disease","volume":"11","author":"Yan","year":"2020","journal-title":"Nat Commun"},{"key":"2025030420232804600_vkae019-B15","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1021\/pr8004919","article-title":"Streptomyces erythraeus trypsin for proteomics applications","volume":"8","author":"Kiser","year":"2009","journal-title":"J Proteome Res"},{"key":"2025030420232804600_vkae019-B16","doi-asserted-by":"crossref","first-page":"a024398","DOI":"10.1101\/cshperspect.a024398","article-title":"The Prion-Like Properties of Amyloid-\u03b2 Assemblies: Implications for Alzheimer's Disease","volume":"6","author":"Walker","year":"2016","journal-title":"Cold Spring Harb Perspect Med"},{"key":"2025030420232804600_vkae019-B17","doi-asserted-by":"crossref","first-page":"778","DOI":"10.3389\/fimmu.2019.00778","article-title":"Sources of type I interferons in infectious immunity: plasmacytoid dendritic cells not always in the driver's seat","volume":"10","author":"Ali","year":"2019","journal-title":"Front Immunol"},{"key":"2025030420232804600_vkae019-B18","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.cell.2011.06.041","article-title":"MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response","volume":"146","author":"Hou","year":"2011","journal-title":"Cell"},{"key":"2025030420232804600_vkae019-B19","doi-asserted-by":"crossref","first-page":"3233","DOI":"10.1038\/s41467-019-11258-x","article-title":"Phosphorylation of MAVS\/VISA by Nemo-like kinase (NLK) for degradation regulates the antiviral innate immune response","volume":"10","author":"Li","year":"2019","journal-title":"Nat Commun"},{"key":"2025030420232804600_vkae019-B20","doi-asserted-by":"crossref","first-page":"949340","DOI":"10.3389\/fncel.2022.949340","article-title":"Type-I interferons in Alzheimer's disease and other tauopathies","volume":"16","author":"Sanford","year":"2022","journal-title":"Front Cell Neurosci"},{"key":"2025030420232804600_vkae019-B21","doi-asserted-by":"crossref","first-page":"3209","DOI":"10.1074\/jbc.M114.593426","article-title":"A role for the adaptor proteins TRAM and TRIF in toll-like receptor 2 signaling","volume":"290","author":"Nilsen","year":"2015","journal-title":"J Biol Chem"},{"key":"2025030420232804600_vkae019-B22","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/j.immuni.2006.04.004","article-title":"The specific and essential role of MAVS in antiviral innate immune responses","volume":"24","author":"Sun","year":"2006","journal-title":"Immunity"},{"key":"2025030420232804600_vkae019-B23","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.3389\/fimmu.2020.01030","article-title":"Regulation of MAVS expression and signaling function in the antiviral innate immune response","volume":"11","author":"Ren","year":"2020","journal-title":"Front Immunol"},{"key":"2025030420232804600_vkae019-B24","doi-asserted-by":"crossref","first-page":"e1501889","DOI":"10.1126\/sciadv.1501889","article-title":"PPM1A silences cytosolic RNA sensing and antiviral defense through direct dephosphorylation of MAVS and TBK1","volume":"2","author":"Xiang","year":"2016","journal-title":"Sci Adv"},{"key":"2025030420232804600_vkae019-B25","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.4049\/jimmunol.1601194","article-title":"TTLL12 inhibits the activation of cellular antiviral signaling through interaction with VISA\/MAVS","volume":"198","author":"Ju","year":"2017","journal-title":"J Immunol"},{"key":"2025030420232804600_vkae019-B26","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.immuni.2016.06.020","article-title":"Post-Translational Modification Control of Innate Immunity","volume":"45","author":"Liu","year":"2016","journal-title":"Immunity"},{"key":"2025030420232804600_vkae019-B27","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1038\/ni.3641","article-title":"The ubiquitin E3 ligase TRIM31 promotes aggregation and activation of the signaling adaptor MAVS through Lys63-linked polyubiquitination","volume":"18","author":"Liu","year":"2017","journal-title":"Nat Immunol"},{"key":"2025030420232804600_vkae019-B28","doi-asserted-by":"crossref","first-page":"aaa2630","DOI":"10.1126\/science.aaa2630","article-title":"Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation","volume":"347","author":"Liu","year":"2015","journal-title":"Science"},{"key":"2025030420232804600_vkae019-B29","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1146\/annurev-med-050715-104343","article-title":"Innate immunity and neurodegeneration","volume":"69","author":"Labzin","year":"2018","journal-title":"Annu Rev Med"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/214\/2\/238\/61945978\/vkae019.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/214\/2\/238\/61945978\/vkae019.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T21:34:05Z","timestamp":1741124045000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/214\/2\/238\/8020943"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,1]]},"references-count":29,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,2,1]]}},"URL":"https:\/\/doi.org\/10.1093\/jimmun\/vkae019","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,2]]},"published":{"date-parts":[[2025,2,1]]}}}