Septins As Modulators of Endo-Lysosomal Membrane Traffic

Abstract

Septins constitute a family of GTP-binding proteins, which assemble into non-polar filaments in a nucleotide-dependent manner. These filaments can be recruited to negatively charged membrane surfaces. When associated with membranes septin filaments can act as diffusion barriers, which confine subdomains of distinct biological functions. In addition, they serve scaffolding roles by recruiting cytosolic proteins and other cytoskeletal elements. Septins have been implicated in a large variety of membrane-dependent processes, including cytokinesis, signaling, cell migration, and membrane traffic, and several family members have been implicated in disease. However, surprisingly little is known about the molecular mechanisms underlying their biological functions. This review summarizes evidence in support of regulatory roles of septins during endo-lysosomal sorting, with a particular focus on phosphoinositides, which serve as spatial landmarks guiding septin recruitment to distinct subcellular localizations.

Keywords: endocytosis; endosome; membrane; phosphoinositides; septins; sorting.

Figure 1

Schematic representation of endosomal sorting events with proven or putative involvement of septins. Septin filaments are indicated in blue, actin filaments in red. SEPT2/7/9/11 promote phagocytosis (A). Through associating with dynamin SEPT5/11 might function during clathrin-mediated endocytosis (B). Interactions of septins with actin filaments might modulate macropinocytosis (C). Complex formation between AP-3 and SEPT6/7 facilitates degradative sorting (D). SEPT2/6/7 promote fusion of macropinosomes (E) and potentially of MVBs with lysosomes (F). PI(5)P at endosomes protects cargo from degradative sorting, and might recruit SEPT9 to sorting endosomes (G). SEPT2/6/7/9 form cages around intracellular pathogens and promote their sorting to autophagosomes (H). SEPT9 inhibits ubiquitylation of EGF receptors at the plasma membrane by associating with CIN85, and thereby attenuates degradative sorting at endosomes (I). See text for details.