RRC ID 60813
Author Takáts S, Lévay L, Boda A, Tóth S, Simon-Vecsei Z, Rubics A, Varga Á, Lippai M, Lőrincz P, Glatz G, Juhász G.
Title The Warburg Micro Syndrome-associated Rab3GAP-Rab18 module promotes autolysosome maturation through the Vps34 Complex I.
Journal FEBS J
Abstract Warburg micro syndrome (WMS) is a hereditary autosomal neuromuscular disorder in humans caused by mutations in Rab18, Rab3GAP1, or Rab3GAP2 genes. 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-Rab18 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-Rab18 module members leads to perturbed autolysosome morphology due to destabilization of Rab7-positive 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-kinase) complexes in fat cells, mimics the autophagic phenotype of Rab3GAP-Rab18 module loss. We find that GTP-bound 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-Rab18 module regulates autolysosomal maturation through its interaction with the Vps34 Complex I, and perturbed autophagy due to loss of the Rab3GAP-Rab18 module may contribute to the development of WMS.
Volume 288(1)
Pages 190-211
Published 2021-1-1
DOI 10.1111/febs.15313
PMID 32248620
MeSH Abnormalities, Multiple / genetics* Abnormalities, Multiple / metabolism Abnormalities, Multiple / pathology Adaptor Proteins, Vesicular Transport / genetics Adaptor Proteins, Vesicular Transport / metabolism Adipocytes / metabolism Adipocytes / pathology Animals Autophagy / genetics Autophagy-Related Proteins / genetics Autophagy-Related Proteins / metabolism Beclin-1 / genetics Beclin-1 / metabolism Cataract / congenital* Cataract / genetics Cataract / metabolism Cataract / pathology Class III Phosphatidylinositol 3-Kinases / deficiency Class III Phosphatidylinositol 3-Kinases / genetics* Cornea / abnormalities* Cornea / metabolism Cornea / pathology Disease Models, Animal Drosophila Proteins / deficiency Drosophila Proteins / genetics* Drosophila Proteins / metabolism Drosophila melanogaster Gene Expression Regulation Humans Hypogonadism / genetics* Hypogonadism / metabolism Hypogonadism / pathology Intellectual Disability / genetics* Intellectual Disability / metabolism Intellectual Disability / pathology Lysosomes / metabolism* Lysosomes / pathology Microcephaly / genetics* Microcephaly / metabolism Microcephaly / pathology Muscles / metabolism Muscles / pathology Neurons / metabolism Neurons / pathology Optic Atrophy / genetics* Optic Atrophy / metabolism Optic Atrophy / pathology Protein Binding Sequence Homology, Amino Acid Signal Transduction Tumor Suppressor Proteins / genetics Tumor Suppressor Proteins / metabolism rab GTP-Binding Proteins / deficiency rab GTP-Binding Proteins / genetics* rab GTP-Binding Proteins / metabolism rab3 GTP-Binding Proteins / deficiency rab3 GTP-Binding Proteins / genetics* rab7 GTP-Binding Proteins
IF 4.739
Times Cited 1
Drosophila 31935R-3