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The P23H rhodopsin knock-in (P23H-KI) mouse develops retinal degeneration that mirrors RP phenotype in patients carrying the orthologous variant. Previously, we found that the P23H rhodopsin protein was degraded in P23H-KI retinas, and the Unfolded Protein Response (UPR) promoted P23H rhodopsin degradation in heterologous cells in vitro. Here, we investigated the role of a UPR regulator gene, activating transcription factor 6 (<jats:italic>Atf6<\/jats:italic>), in rhodopsin protein homeostasis in heterozygous P23H rhodopsin (<jats:italic>Rho<\/jats:italic><jats:sup>+<jats:italic>\/P23H<\/jats:italic><\/jats:sup>) mice. Significantly increased rhodopsin protein levels were found in <jats:italic>Atf6<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup><jats:italic>Rho<\/jats:italic><jats:sup>+<jats:italic>\/P23H<\/jats:italic><\/jats:sup> retinas compared to <jats:italic>Atf6<\/jats:italic><jats:sup>+<jats:italic>\/\u2212<\/jats:italic><\/jats:sup><jats:italic>Rho<\/jats:italic><jats:sup>+<jats:italic>\/P23H<\/jats:italic><\/jats:sup> retinas at early ages (~\u2009P12), while <jats:italic>rhodopsin<\/jats:italic> mRNA levels were not different. The IRE1 pathway of the UPR was hyper-activated in young <jats:italic>Atf6<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup><jats:italic>Rho<\/jats:italic><jats:sup>+<jats:italic>\/P23H<\/jats:italic><\/jats:sup> retinas, and photoreceptor layer thickness was unchanged at this early age in <jats:italic>Rho<\/jats:italic><jats:sup>+<jats:italic>\/P23H<\/jats:italic><\/jats:sup> mice lacking <jats:italic>Atf6<\/jats:italic>. By contrast, older <jats:italic>Atf6<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup><jats:italic>Rho<\/jats:italic><jats:sup>+<jats:italic>\/P23H<\/jats:italic><\/jats:sup> mice developed significantly increased retinal degeneration in comparison to <jats:italic>Atf6<\/jats:italic><jats:sup>+<jats:italic>\/\u2212<\/jats:italic><\/jats:sup><jats:italic>Rho<\/jats:italic><jats:sup>+<jats:italic>\/P23H<\/jats:italic><\/jats:sup> mice in all retinal layers, accompanied by reduced rhodopsin protein levels. Our findings demonstrate that <jats:italic>Atf6<\/jats:italic> is required for efficient clearance of rhodopsin protein in rod photoreceptors expressing P23H rhodopsin, and that loss of <jats:italic>Atf6<\/jats:italic> ultimately accelerates retinal degeneration in P23H-KI mice.<\/jats:p>","DOI":"10.1038\/s41598-021-95895-7","type":"journal-article","created":{"date-parts":[[2021,8,11]],"date-time":"2021-08-11T10:09:03Z","timestamp":1628676543000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["ATF6 is required for efficient rhodopsin clearance and retinal homeostasis in the P23H rho retinitis pigmentosa mouse model"],"prefix":"10.1038","volume":"11","author":[{"given":"Eun-Jin","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priscilla","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leon","family":"Chea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randal J.","family":"Kaufman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan H.","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,8,11]]},"reference":[{"key":"95895_CR1","first-page":"1659","volume":"34","author":"EL Berson","year":"1993","unstructured":"Berson, E. 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