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Genes mutated in BBS encode for components and regulators of the BBSome, an octameric complex that controls the trafficking of cargos and receptors within the primary cilium. Although both structure and function of the BBSome have been extensively studied, the impact of ubiquitin signaling on BBSome is largely unknown. We identify the E3 ubiquitin ligase PJA2 as a novel resident of the ciliary compartment and regulator of the BBSome. Upon GPCR\u2010cAMP stimulation, PJA2 ubiquitylates BBSome subunits. We demonstrate that ubiquitylation of BBS1 at lysine 143 increases the stability of the BBSome and promotes its binding to BBS3, an Arf\u2010like GTPase protein controlling the targeting of the BBSome to the ciliary membrane. Downregulation of\n                    <jats:italic>PJA2<\/jats:italic>\n                    or expression of a ubiquitylation\u2010defective BBS1 mutant (BBS1\n                    <jats:sup>K143R<\/jats:sup>\n                    ) affects the trafficking of G\u2010protein\u2010coupled receptors (GPCRs) and Shh\u2010dependent gene transcription. Expression of BBS1\n                    <jats:sup>K143R<\/jats:sup>\n                    <jats:italic>in\u00a0vivo<\/jats:italic>\n                    impairs cilium formation, embryonic development, and photoreceptors' morphogenesis, thus recapitulating the BBS phenotype in the medaka fish model.\n                  <\/jats:p>","DOI":"10.15252\/embr.202255571","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T03:31:03Z","timestamp":1675654263000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Ubiquitylation of BBSome is required for ciliary assembly and signaling"],"prefix":"10.1038","volume":"24","author":[{"given":"Francesco","family":"Chiuso","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossella","family":"delle Donne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3101-4697","authenticated-orcid":false,"given":"Giuliana","family":"Giamundo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Rinaldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenica","family":"Borzacchiello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Moraca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5256-3188","authenticated-orcid":false,"given":"Daniela","family":"Intartaglia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Iannucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela","family":"Senatore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Lignitto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7089-196X","authenticated-orcid":false,"given":"Corrado","family":"Garbi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5440-6167","authenticated-orcid":false,"given":"Paolo","family":"Conflitti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7532-6959","authenticated-orcid":false,"given":"Bruno","family":"Catalanotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8968-9021","authenticated-orcid":false,"given":"Ivan","family":"Conte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7932-2170","authenticated-orcid":false,"given":"Antonio","family":"Feliciello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,2,6]]},"reference":[{"key":"BFEMBR202255571_CR1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","volume":"1\u20102","author":"M Abraham","year":"2015","unstructured":"Abraham M, Murtola T, Schulz R, P\u00e1ll S, Smith J, Hess B, Lindahl E (2015) GROMACS: high performance molecular simulations through multi\u2010level parallelism from laptops to supercomputers. 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