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We previously showed constitutive activation of the endoplasmic reticulum unfolded protein response (UPR<jats:sup>ER<\/jats:sup>) transcription factor XBP-1s rescues tauopathy-related proteostatic disruption in a tau transgenic <jats:italic>Caenorhabditis elegans<\/jats:italic> (<jats:italic>C. elegans<\/jats:italic>) model of human tauopathy. XBP-1s promotes clearance of pathological tau, and loss of function of the ATF-6 branch of the UPR<jats:sup>ER<\/jats:sup> prevents XBP-1s rescue of tauopathy in <jats:italic>C. elegans<\/jats:italic>. We conducted transcriptomic analysis of tau transgenic and <jats:italic>xbp-1s<\/jats:italic> transgenic <jats:italic>C. elegans<\/jats:italic> and found 116 putative target genes significantly upregulated by constitutively active XBP-1s. Among these were five candidate XBP-1s target genes with human orthologs and a previously known association with ATF6 (<jats:italic>csp-1<\/jats:italic>, <jats:italic>dnj-28<\/jats:italic>, <jats:italic>hsp-4<\/jats:italic>, <jats:italic>ckb-2<\/jats:italic>, and <jats:italic>lipl-3<\/jats:italic>). We examined the functional involvement of these targets in XBP-1s-mediated tauopathy suppression and found loss of function in any one of these genes completely disrupts XBP-1s suppression of tauopathy. Further, we demonstrate upregulation of HSP-4, <jats:italic>C. elegans<\/jats:italic> BiP, partially rescues tauopathy independent of other changes in the transcriptional network. Understanding how the UPR<jats:sup>ER<\/jats:sup> modulates pathological tau accumulation will inform neurodegenerative disease mechanisms and direct further study in mammalian systems with the long-term goal of identifying therapeutic targets in human tauopathies.<\/jats:p>","DOI":"10.1038\/s42003-024-06570-2","type":"journal-article","created":{"date-parts":[[2024,7,26]],"date-time":"2024-07-26T17:01:40Z","timestamp":1722013300000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Endoplasmic reticulum unfolded protein response transcriptional targets of XBP-1s mediate rescue from tauopathy"],"prefix":"10.1038","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8873-4185","authenticated-orcid":false,"given":"Sarah M.","family":"Waldherr","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleen D.","family":"Saxton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor A.","family":"Vadset","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela J.","family":"McMillan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanna M.","family":"Wheeler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole F.","family":"Liachko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2252-7634","authenticated-orcid":false,"given":"Brian C.","family":"Kraemer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,25]]},"reference":[{"key":"6570_CR1","doi-asserted-by":"publisher","first-page":"3400","DOI":"10.1016\/j.bmc.2013.01.056","volume":"21","author":"A Ciechanover","year":"2013","unstructured":"Ciechanover, A. 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