INTRA-ENDOSOMAL MEMBRANE TRAFFIC. Jean Gruenberg. Biochem. Dept., Univ. of Geneva, 30 quai E. Ansermet, 1211-Geneva-4, Switzerland.

Cell surface receptors endocytosed in animal cells first appear in early endosomes. Then, some receptors are recycled back to the cell surface for reutilization, while down-regulated signaling receptors are selectively transported to late endosomes and lysosomes for degradation. Major progress has been made in understanding the mechanism of protein sorting along the latter degradation pathway. The epidermal growth factor (EGF) receptor and other ubiquitinylated down-regulated receptors are first sorted into membrane invaginations and vesicles within multivesicular endosomes via the sequential action of Hrs and ESCRT complexes. Then, these lumenal vesicles and their protein cargo are delivered to late endosomes and lysosomes for degradation. In mammalian cells, however, the lumenal vesicles of late (multivesicular) endosomes, also contain proteins and lipids that are not destined for degradation — including some that are exported to other intracellular destinations. To investigate the dynamic properties of these lumenal membranes, we followed the infectious pathway of vesicular stomatitis virus. We found that fusion of the viral envelope with endosomal membranes and nucleocapsid release are not concomitant events, but occur sequentially, at two successive steps of the endocytic pathway. Fusion already occurs in transport intermediates between early and late endosomes, presumably releasing the nucleocapsid within the lumen of intra-endosomal vesicles, where it remains hidden. Transport to late endosomes is then required for the nucleocapsid to be delivered to the cytoplasm. There, fusion of lumenal vesicles with the endosome limiting membrane presumably releases capsids into the cytosol in a process that depends on the late endosomal phospholipid LBPA and its putative effector Alix/AIP1, thereby initiating infection. The “intra-endosomal” transport of EGF receptor and viral capsids will be discussed, as will possible mechanisms that may regulate the formation and dynamics of lumenal membranes at the different stages of the endocytic pathway.

van der Goot, F. G., and Gruenberg, J. 2006. Intra-endosomal membrane traffic. Trends Cell Biol 16, 514-521.

Gruenberg, J., and Van Der Goot, F. G. 2006. Mechanisms of pathogen entry through the endosomal compartments. Nat Rev Mol Cell Biol 7, 495-504.