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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,6,24]]},"abstract":"<jats:p>\n                    How tick-borne pathogens interact with their hosts has been primarily studied in vertebrates where disease is observed. Comparatively less is known about pathogen interactions within the tick. Here, we report that\n                    <jats:italic toggle=\"yes\">Ixodes scapularis<\/jats:italic>\n                    ticks infected with either\n                    <jats:italic toggle=\"yes\">Anaplasma phagocytophilum<\/jats:italic>\n                    (causative agent of anaplasmosis) or\n                    <jats:italic toggle=\"yes\">Borrelia burgdorferi<\/jats:italic>\n                    (causative agent of Lyme disease) show activation of the ATF6 branch of the unfolded protein response (UPR). Disabling ATF6 functionally restricts pathogen survival in ticks. When stimulated, ATF6 functions as a transcription factor, but is the least understood out of the three UPR pathways. To interrogate the\n                    <jats:italic toggle=\"yes\">Ixodes<\/jats:italic>\n                    ATF6 transcriptional network, we developed a custom R script to query tick promoter sequences. This revealed\n                    <jats:italic toggle=\"yes\">stomatin<\/jats:italic>\n                    as a potential gene target, which has roles in lipid homeostasis and vesical transport.\n                    <jats:italic toggle=\"yes\">Ixodes stomatin<\/jats:italic>\n                    was experimentally validated as a bona fide ATF6-regulated gene through luciferase reporter assays, pharmacological activators, RNA interference transcriptional repression, and immunofluorescence microscopy. Silencing\n                    <jats:italic toggle=\"yes\">stomatin<\/jats:italic>\n                    decreased\n                    <jats:italic toggle=\"yes\">A. phagocytophilum<\/jats:italic>\n                    colonization in\n                    <jats:italic toggle=\"yes\">Ixodes<\/jats:italic>\n                    and disrupted cholesterol dynamics in tick cells. Furthermore, blocking\n                    <jats:italic toggle=\"yes\">stomatin<\/jats:italic>\n                    restricted cholesterol availability to the bacterium, thereby inhibiting growth and survival. Taken together, we have identified the\n                    <jats:italic toggle=\"yes\">Ixodes<\/jats:italic>\n                    ATF6 pathway as a contributor to vector competence through Stomatin-regulated cholesterol homeostasis. Moreover, our custom, web-based transcription factor binding site search tool \u201cArthroQuest\u201d revealed that the ATF6-regulated nature of\n                    <jats:italic toggle=\"yes\">stomatin<\/jats:italic>\n                    is unique to blood-feeding arthropods. Collectively, these findings highlight the importance of studying fundamental processes in nonmodel organisms.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2501045122","type":"journal-article","created":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T13:34:32Z","timestamp":1750167272000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":5,"title":["ATF6 enables pathogen infection in ticks by inducing\n                    <i>stomatin<\/i>\n                    and altering cholesterol dynamics"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2865-7031","authenticated-orcid":false,"given":"Kaylee A.","family":"Vosbigian","sequence":"first","affiliation":[{"name":"Department of Veterinary Microbiology and Pathology, College of Veterinary Sciences, Washington State University","place":["Pullman"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9766-4714","authenticated-orcid":false,"given":"Sarah J.","family":"Wright","sequence":"additional","affiliation":[{"name":"Department of Veterinary Microbiology and Pathology, College of Veterinary Sciences, Washington State University","place":["Pullman"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7992-004X","authenticated-orcid":false,"given":"Brianna P.","family":"Steiert","sequence":"additional","affiliation":[{"name":"Department of Veterinary Microbiology and Pathology, College of Veterinary Sciences, Washington State University","place":["Pullman"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6127-4363","authenticated-orcid":false,"given":"Kristin L.","family":"Rosche","sequence":"additional","affiliation":[{"name":"Department of Veterinary Microbiology and Pathology, College of Veterinary Sciences, Washington State University","place":["Pullman"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elis A.","family":"Fisk","sequence":"additional","affiliation":[{"name":"Department of Veterinary Microbiology and Pathology, College of Veterinary Sciences, Washington State University","place":["Pullman"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Ramirez-Zepp","sequence":"additional","affiliation":[{"name":"Department of Veterinary Microbiology and Pathology, College of Veterinary Sciences, Washington State University","place":["Pullman"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9050-5277","authenticated-orcid":false,"given":"Jason M.","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Veterinary Microbiology and Pathology, College of Veterinary Sciences, Washington State University","place":["Pullman"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric A.","family":"Shelden","sequence":"additional","affiliation":[{"name":"School of Molecular Biosciences, College of Veterinary Sciences, Washington State University","place":["Pullman"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5212-2494","authenticated-orcid":false,"given":"Dana K.","family":"Shaw","sequence":"additional","affiliation":[{"name":"Department of Veterinary Microbiology and Pathology, College of Veterinary Sciences, Washington State University","place":["Pullman"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,6,17]]},"reference":[{"key":"e_1_3_4_1_2","unstructured":"CDC Tickborne diseases of the United States. 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