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Here, we systematically investigated the role of E3 ubiquitin ligases, key regulators of protein degradation-mediated proteostasis, in presynaptic homeostatic plasticity (PHP). An electrophysiology-based genetic screen of 157 E3 ligase-encoding genes at the\n                    <jats:italic>Drosophila<\/jats:italic>\n                    neuromuscular junction identified\n                    <jats:italic>thin<\/jats:italic>\n                    , an ortholog of human\n                    <jats:italic>tripartite motif-containing 32<\/jats:italic>\n                    (\n                    <jats:italic>TRIM32<\/jats:italic>\n                    ), a gene implicated in several neurological disorders, including autism spectrum disorder and schizophrenia. We demonstrate that\n                    <jats:italic>thin<\/jats:italic>\n                    functions presynaptically during rapid and sustained PHP. Presynaptic\n                    <jats:italic>thin<\/jats:italic>\n                    negatively regulates neurotransmitter release under baseline conditions by limiting the number of release-ready vesicles, largely independent of gross morphological defects. We provide genetic evidence that\n                    <jats:italic>thin<\/jats:italic>\n                    controls release through\n                    <jats:italic>dysbindin<\/jats:italic>\n                    , a schizophrenia-susceptibility gene required for PHP. Thin and Dysbindin localize in proximity within presynaptic boutons, and Thin degrades Dysbindin in vitro. Thus, the E3 ligase Thin links protein degradation-dependent proteostasis of Dysbindin to homeostatic regulation of neurotransmitter release.\n                  <\/jats:p>","DOI":"10.7554\/elife.71437","type":"journal-article","created":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T06:15:13Z","timestamp":1657174513000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.71437","source":"Crossref","is-referenced-by-count":15,"title":["The E3 ligase Thin controls homeostatic plasticity through neurotransmitter release repression"],"prefix":"10.7554","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4143-4166","authenticated-orcid":true,"given":"Martin","family":"Baccino-Calace","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02crff812","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular Life Sciences, University of Zurich","place":["Zurich, Switzerland"]},{"name":"Zurich Ph.D. Program in Molecular Life Sciences","place":["Zurich, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2797-9952","authenticated-orcid":true,"given":"Katharina","family":"Schmidt","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02crff812","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular Life Sciences, University of Zurich","place":["Zurich, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1624-6761","authenticated-orcid":true,"given":"Martin","family":"M\u00fcller","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02crff812","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular Life Sciences, University of Zurich","place":["Zurich, Switzerland"]},{"name":"Zurich Ph.D. Program in Molecular Life Sciences","place":["Zurich, Switzerland"]},{"id":[{"id":"https:\/\/ror.org\/02crff812","id-type":"ROR","asserted-by":"publisher"}],"name":"Neuroscience Center Zurich, University of Zurich\/ETH Zurich","place":["Zurich, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2022,7,7]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"1607","DOI":"10.1038\/nprot.2014.105","article-title":"Generation of a transgenic ORFeome library in Drosophila","volume":"9","author":"Bischof","year":"2014","journal-title":"Nature Protocols"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1111\/j.1365-2818.2006.01706.x","article-title":"A guided tour into subcellular colocalization analysis in light microscopy","volume":"224","author":"Bolte","year":"2006","journal-title":"Journal of Microscopy"},{"key":"bib3","article-title":"pwr: Basic Functions for Power Analysis","author":"Champely","year":"2020","unstructured":"Champely S. 2020. pwr: Basic Functions for Power Analysis. 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