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They are also key elements in understanding disease mechanisms and developing therapeutic strategies. We have previously reported that ubiquitin-like 3 (UBL3) serves as a novel post-translational modifier that is highly expressed in the cerebral cortex and hippocampus, in addition to various other organs, and that 60% of proteins contained in small extracellular vesicles (sEVs), including exosomes, are influenced by UBL3. In this study, we generated transgenic mice expressing biotinylated UBL3 in the forebrain under control of the alpha-CaMKII promoter (\n                    <jats:italic>Ubl3<\/jats:italic>\n                    <jats:sup>Tg\/+<\/jats:sup>\n                    ). Western blot analysis revealed that the expression of UBL3 in the cerebral cortex and hippocampus was 6- to 7-fold higher than that in the cerebellum. Therefore, we performed immunoprecipitation of protein extracts from the cerebral cortex of\n                    <jats:italic>Ubl3<\/jats:italic>\n                    <jats:sup>+\/+<\/jats:sup>\n                    and\n                    <jats:italic>Ubl3<\/jats:italic>\n                    <jats:sup>Tg\/+<\/jats:sup>\n                    mice using avidin beads to comprehensively discover UBL3 interacting proteins, identifying 35 new UBL3 interacting proteins. Nine proteins were annotated as extracellular exosomes. Gene Ontology (GO) analysis suggested a new relationship between sEVs and RNA metabolism in neurodegenerative diseases. We confirmed the association of endogenous UBL3 with the RNA-binding proteins FUS and HPRT1\u2014both listed in the Neurodegenerative Diseases Variation Database (NDDVD)\u2014and with LYPLA1, which is involved in Huntington\u2019s disease, using immunoprecipitation (IP)-western blotting analysis. These UBL3 interacting proteins will accelerate the continued elucidation of sEV research about proteins regulated by novel post-translational modifications by UBL3 in the brain.\n                  <\/jats:p>","DOI":"10.1186\/s13041-024-01131-4","type":"journal-article","created":{"date-parts":[[2024,8,15]],"date-time":"2024-08-15T05:02:25Z","timestamp":1723698145000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Comprehensive identification of ubiquitin-like 3 (UBL3)-interacting proteins in the mouse brain"],"prefix":"10.1186","volume":"17","author":[{"given":"Hiroshi","family":"Ageta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoki","family":"Nishioka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisateru","family":"Yamaguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunihiro","family":"Tsuchida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2543-4828","authenticated-orcid":false,"given":"Natsumi","family":"Ageta-Ishihara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,8,15]]},"reference":[{"key":"1131_CR1","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1038\/nsmb.1842","volume":"17","author":"YL Deribe","year":"2010","unstructured":"Deribe YL, Pawson T, Dikic I. Post-translational modifications in signal integration. Nat Struct Mol Biol. 2010;17:666\u201372.","journal-title":"Nat Struct Mol Biol"},{"key":"1131_CR2","doi-asserted-by":"publisher","first-page":"4829","DOI":"10.1007\/s00018-019-03246-7","volume":"76","author":"H Ageta","year":"2019","unstructured":"Ageta H, Tsuchida K. Post-translational modification and protein sorting to small extracellular vesicles including exosomes by ubiquitin and UBLs. Cell Mol Life Sci. 2019;76:4829\u201348.","journal-title":"Cell Mol Life Sci"},{"key":"1131_CR3","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1038\/nrm3255","volume":"13","author":"IM Ahearn","year":"2011","unstructured":"Ahearn IM, Haigis K, Bar-Sagi D, Philips MR. Regulating the regulator: post-translational modification of RAS. 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The experimental protocols were approved by the Animal Care Committee of Laboratory Animals of the Fujita Health University (AP23003).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"There are no competing interests to declare in relation to this manuscript.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"57"}}