Septin6 and Septin7 GTP binding proteins regulate AP-3- and ESCRT-dependent multivesicular body biogenesis.
Septins (SEPTs) form a family of GTP-binding proteins implicated in cytoskeleton and membrane organization, cell division and host/pathogen interactions. The precise function of many family members remains elusive. We show that SEPT6 and SEPT7 complexes bound to F-actin regulate protein sorting during multivesicular body (MVB) biogenesis. These complexes bind AP-3, an adapter complex sorting cargos destined to remain in outer membranes of maturing endosomes, modulate AP-3 membrane interactions and the motility of AP-3-positive endosomes. These SEPT-AP interactions also influence the membrane interaction of ESCRT (endosomal-sorting complex required for transport)-I, which selects ubiquitinated cargos for degradation inside MVBs. Whereas our findings demonstrate that SEPT6 and SEPT7 function in the spatial, temporal organization of AP-3- and ESCRT-coated membrane domains, they uncover an unsuspected coordination of these sorting machineries during MVB biogenesis. This requires the E3 ubiquitin ligase LRSAM1, an AP-3 interactor regulating ESCRT-I sorting activity and whose mutations are linked with Charcot-Marie-Tooth neuropathies.
Biotechnological Center, Technische Universität Dresden, Dresden, Germany.
Sofia
S
Traikov
Biotechnological Center, Technische Universität Dresden, Dresden, Germany.
Christoph
C
Stange
Biotechnological Center, Technische Universität Dresden, Dresden, Germany; School of Life and Health Sciences, Aston University, Birmingham, United Kingdom.
Thomas
T
Wassmer
Molecular Mechanisms of Intracellular Transport Laboratory, CNRS-Institut Curie, Paris, France; Cell and Tissue Imaging Facility, PICT-IBiSA & Nikon Imaging Center, CNRS-Institut Curie, Paris, France.
Perrine
P
Paul-Gilloteaux
Molecular Mechanisms of Intracellular Transport Laboratory, CNRS-Institut Curie, Paris, France; Cell and Tissue Imaging Facility, PICT-IBiSA & Nikon Imaging Center, CNRS-Institut Curie, Paris, France.
Jean
J
Salamero
Molecular Mechanisms of Intracellular Transport Laboratory, CNRS-Institut Curie, Paris, France.
Graça
G
Raposo
Biotechnological Center, Technische Universität Dresden, Dresden, Germany.
Bernard
B
Hoflack
D000199:Actins / Q000378:metabolism; D033963:Adaptor Protein Complex 3 / Q000378:metabolism*; D001692:Biological Transport; D018797:Cell Cycle Proteins / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D009068:Movement; D057146:Multivesicular Bodies / Q000378:metabolism*; D011485:Protein Binding; D058112:Septins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D000199:Actins; D033963:Adaptor Protein Complex 3; D018797:Cell Cycle Proteins; D056827:Endosomal Sorting Complexes Required for Transport; C489657:LRSAM1 protein, human; D044767:Ubiquitin-Protein Ligases; C436485:SEPTIN6 protein, human; C113158:SEPTIN7 protein, human; D058112:Septins