title: AP-1/σ1A and AP-1/σ1B adaptor-proteins differentially regulate neuronal early endosome maturation via the Rab5/Vps34-pathway.
abstract: The σ1 subunit of the AP-1 clathrin-coated-vesicle adaptor-protein complex is expressed as three isoforms. Tissues express σ1A and one of the σ1B and σ1C isoforms. Brain is the tissue with the highest σ1A and σ1B expression. σ1B-deficiency leads to severe mental retardation, accumulation of early endosomes in synapses and fewer synaptic vesicles, whose recycling is slowed down. AP-1/σ1A and AP-1/σ1B regulate maturation of these early endosomes into multivesicular body late endosomes, thereby controlling synaptic vesicle protein transport into a degradative pathway. σ1A binds ArfGAP1, and with higher affinity brain-specific ArfGAP1, which bind Rabex-5. AP-1/σ1A-ArfGAP1-Rabex-5 complex formation leads to more endosomal Rabex-5 and enhanced, Rab5(GTP)-stimulated Vps34 PI3-kinase activity, which is essential for multivesicular body endosome formation. Formation of AP-1/σ1A-ArfGAP1-Rabex-5 complexes is prevented by σ1B binding of Rabex-5 and the amount of endosomal Rabex-5 is reduced. AP-1 complexes differentially regulate endosome maturation and coordinate protein recycling and degradation, revealing a novel molecular mechanism by which they regulate protein transport besides their established function in clathrin-coated-vesicle formation.
authors.affiliation: Georg-August University Göttingen, Department for Cellular Biochemistry, Humboldtallee 23, D-37073 Göttingen, Germany.
authors.forename: Ermes
authors.initials: E
authors.lastname: Candiello
authors.affiliation: Georg-August University Göttingen, Department for Cellular Biochemistry, Humboldtallee 23, D-37073 Göttingen, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Kratzke
authors.affiliation: Electron microscopy, Max-Planck-Institut for Biophysical Chemistry, Am Fassberg 11, D-37077 Göttingen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Wenzel
authors.affiliation: Israel Institute of Technology, Department Biology, Haifa 32000, Israel.
authors.forename: Dan
authors.initials: D
authors.lastname: Cassel
authors.affiliation: Georg-August University Göttingen, Department for Cellular Biochemistry, Humboldtallee 23, D-37073 Göttingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schu
mesh_terms: D034002:Adaptor Protein Complex sigma Subunits / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism* / Q000648:ultrastructure; D020690:GTPase-Activating Proteins / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D018345:Mice, Knockout; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D015398:Signal Transduction; D013574:Synaptosomes / Q000378:metabolism
chemical_list: D034002:Adaptor Protein Complex sigma Subunits; C503238:Arfgap1 protein, mouse; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D046912:Multiprotein Complexes; C510870:RabGEF1 protein, mouse; D058546:Class III Phosphatidylinositol 3-Kinases