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Rab3GAP1\/2 forms a heterodimeric complex, which acts as a guanosine nucleotide exchange factor and activates Rab18. Although the genetic causes of WMS are known, it is still unclear whether loss of the Rab3GAP\u2010Rab18 module affects neuronal or muscle cell physiology or both, and how. In this work, we characterize a Rab3GAP2 mutant Drosophila line to establish a novel animal model for WMS. Similarly to symptoms of WMS, loss of Rab3GAP2 leads to highly decreased motility in Drosophila that becomes more serious with age. We demonstrate that these mutant flies are defective for autophagic degradation in multiple tissues including fat cells and muscles. Loss of Rab3GAP\u2010Rab18 module members leads to perturbed autolysosome morphology due to destabilization of Rab7\u2010positive autophagosomal and late endosomal compartments and perturbation of lysosomal biosynthetic transport. Importantly, overexpression of UVRAG or loss of Atg14, two alternative subunits of the Vps34\/PI3K (vacuole protein sorting 34\/phosphatidylinositol 3\u2010kinase) complexes in fat cells, mimics the autophagic phenotype of Rab3GAP\u2010Rab18 module loss. We find that GTP\u2010bound Rab18 binds to Atg6\/Beclin1, a permanent subunit of Vps34 complexes. Finally, we show that Rab3GAP2 and Rab18 are present on autophagosomal and autolysosomal membranes and colocalize with Vps34 Complex I subunits. Our data suggest that the Rab3GAP\u2010Rab18 module regulates autolysosomal maturation through its interaction with the Vps34 Complex I, and perturbed autophagy due to loss of the Rab3GAP\u2010Rab18 module may contribute to the development of WMS.<\/jats:p>","DOI":"10.1111\/febs.15313","type":"journal-article","created":{"date-parts":[[2020,4,5]],"date-time":"2020-04-05T05:57:04Z","timestamp":1586066224000},"page":"190-211","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["The Warburg Micro Syndrome\u2010associated Rab3GAP\u2010Rab18 module promotes autolysosome maturation through the Vps34 Complex I"],"prefix":"10.1111","volume":"288","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2139-7740","authenticated-orcid":false,"given":"Szabolcs","family":"Tak\u00e1ts","sequence":"first","affiliation":[{"name":"Department of Anatomy, Cell and Developmental Biology ELTE E\u00f6tv\u00f6s Lor\u00e1nd University Budapest 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