Endosomal carriers can also fuse with each other to create EEs. As cargo enters the endosome, the lumenal pH is rapidly and progressively acidified (pH of EE ∼pH 6) with the lowest pH found in lysosomes (pH < 5). Acidification plays an important functional role as it affects binding affinities for ligands in the

lumen as well as the activity of lumenal enzymes (Van Dyke, 1996). From the EE, cargos can be trafficked to LE and lysosomes via multivesicular bodies (MVBs), to REs via tubular intermediates, or back to the plasma membrane directly from the EE (Jovic et al., 2010). Recycling to the plasma membrane, therefore, can occur from both the EE and the RE. The EE Ruxolitinib research buy usually returns endocytosed receptors rapidly to the same place from where they were first endocytosed. Recycling from the RE is slower find more and returns internalized cargos to multiple locations on the surface. The regulated routing through these various

endosomes endows endosomes with the capacity to finely tune the distribution of receptors and the extent of signaling (Huotari and Helenius, 2011; Figure 2). How do endosomes maintain compartment identity in the face of continuous flux of their components? How is directionality and specificity of transport ensured and how is polarized sorting to distinct endosomal compartments regulated? Why do late endosomes not fuse with the nucleus or another inappropriate compartment? The answer to these questions is complex, but some answers are becoming apparent. A large number of protein families are necessary to ensure correct vesicular transport of membrane cargos, such as the small GTPase families Arfs and rabs, tethering proteins such as exocyst complex, actin cytoskeleton regulators, and SPTLC1 others. The coordinated action of these proteins ensures specificity and directionality of fission, transport, and fusion. Excellent reviews of the detailed molecular mechanisms unraveled to date exist on these different classes of proteins (Brett and Traub, 2006, Brunger, 2005, Di Paolo and De Camilli,

2006, Fölsch, 2005, Grant and Caplan, 2008, Huotari and Helenius, 2011, Miaczynska et al., 2004, Myers and Casanova, 2008, Prinz and Hinshaw, 2009 and Schafer, 2004), and we will only touch on some of them as a way of exemplifying overarching ideas. Some of the mechanisms thought to impose specificity and selectivity upon a transport step include phosphoinositide composition, regulated membrane deformation, and the sequential assembly of regulatory platforms (Krauss and Haucke, 2012). All of these mechanisms are in effect throughout cellular membrane transport processes, not just the endosome. Modifying lipid composition and partitioning into distinct lipid domains are common mechanisms for creating distinct compartments. The lipid composition, especially in terms of phosphoinositides, is distinct for different compartments (Di Paolo and De Camilli, 2006).