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Beyond its synaptic localization, STX3 is also detected in the photoreceptor inner segment, where its function remains poorly understood. It is shown that STX3 interacts with rhodopsin, peripherin 2, and the rod outer segment protein 1. In rod\u2010specific STX3 knockout retinas, these proteins are mislocalized, whereas cone opsins remain properly localized, suggesting a distinct STX3 function in cones. To further define its cone\u2010specific dysfunction, a cone\u2010specific STX3 knockout mouse is generated. This model exhibited early cone dysfunction followed by progressive rod impairment and photoreceptor degeneration. Cone degeneration correlated with early abnormalities in the connecting cilium. Specifically, a selective depletion of syntaxin binding protein 1 (STXBP1) and cone arrestin 4 is observed, a phenotype not seen when STX3 is specifically eliminated in rods. A light\u2010dependent complex comprising STX3, STXBP1, and arrestin 4 is further identified, with arrestin 4 preferentially associating with STX3 in the dark\u2010adapted retina and with STXBP1 in the light\u2010adapted retina. These findings reveal a cone\u2010specific, light\u2010regulated protein interaction network essential for cone function and survival, highlighting distinct and context\u2010dependent roles of STX3 in rods and cones.<\/jats:p>","DOI":"10.1002\/advs.202513319","type":"journal-article","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T08:13:29Z","timestamp":1762935209000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Syntaxin 3B Mediates Light\u2010Dependent Interactions with STXBP1 and Arrestin 4: Distinct Roles in Rods and Cones"],"prefix":"10.1002","volume":"13","author":[{"given":"Lars","family":"Tebbe","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering University of Houston  Houston TX 77204 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larissa","family":"Ikelle","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering University of Houston  Houston TX 77204 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa S.","family":"Makia","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering University of Houston  Houston TX 77204 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mashal","family":"Kakakhel","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering University of Houston  Houston TX 77204 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muayyad R.","family":"Al\u2010Ubaidi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering University of Houston  Houston TX 77204 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6534-5144","authenticated-orcid":false,"given":"Muna I.","family":"Naash","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering University of Houston  Houston TX 77204 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,12]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2024.1380064"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2013.09.006"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells8040337"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells8080780"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201810099"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2020.1823124"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11320"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.10.022"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biophys-070816-034117"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12188-4"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biophys-111821-104732"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2004.11.009"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2012.03.009"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2012.10.001"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1107\/S2052252514020727"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/18.16.4372"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2013.02.004"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.16-21-06713.1996"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2202-7-54"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2009.12.075"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0952523807070198"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.21806"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00026.2018"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.039982"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.222034"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0138508"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2010751117"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2015.12.002"},{"key":"e_1_2_9_29_1","first-page":"50","volume":"28","author":"Molday R. 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