Abstract
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.
Highlights
Septins (SEPTs) comprise a family of GTP-binding proteins that assemble into oligomers and form higher-order structures in vitro [1,2]
We previously found that SEPT6, SEPT7 or BORG4 are involved in the AP-3-dependent, lysosomal targeting of Lysosomal-associated membrane protein 1 (LAMP1), a protein destined to remind in the outer membrane of late endosomal compartments [32]
We measured the release of Gag viruslike particles (VLP) from HeLa cells depleted in SEPT6, SEPT7, BORG4, AP-3 or Rab7 (
Summary
Septins (SEPTs) comprise a family of GTP-binding proteins that assemble into oligomers and form higher-order structures in vitro [1,2]. Transmembrane proteins are sorted in early endosomes to different destinations, either back to the cell surface or to the trans-Golgi network (TGN) or to late endocytic compartments for degradation. Transport from early to late endosomes is a complex membrane maturation process involving the formation of multivesicular bodies (MVBs). During this process, transmembrane cargos destined to remain in the outer membrane of late endocytic compartments such as lysosome membrane proteins (LAMPs) are segregated away from cargos destined for degradation inside maturing early endosomes. It requires membrane binding to cytoskeleton elements, in particular a switch from F-actin, which maintains early endosomes in the cell periphery [29] to microtubules needed for MVB transport to perinuclear late endocytic compartments [30]
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