Available online at www.sciencedirect.com Viruses and endosome membrane dynamics Jean Gruenberg Cell surface molecules, ligands, and solutes can be endocytosed into animal cells via several pathways in addition to clathrin-mediated endocytosis, which all seem to lead to canonical endosomes. It seems that viruses can enter and infect cells through most of, if not all, endocytic routes, having evolved different, sometimes elaborate, strategies to (mis)use cellular machineries to their own benefit during infection. In this short review, I will discuss recent progress in understanding the pathways followed by animal viruses into cells, and how these studies are also providing novel insights into our understanding of some molecular mechanisms that control endocytic membrane transport. Addresses Department of Biochemistry, University of Geneva, 30 quai E. Ansermet, 1211 Geneva 4, Switzerland Corresponding author: Gruenberg, Jean (jean.gruenberg@unige.ch) Current Opinion in Cell Biology 2009, 21:582–588 This review comes from a themed issue on Membranes and organelles Edited by Greg Odorizzi and Peter Rehling Available online 13th May 2009 0955-0674/$ – see front matter # 2009 Elsevier Ltd. All rights reserved. DOI 10.1016/j.ceb.2009.03.008 The endocytic pathway Cell surface lipids and proteins as well as solutes are endocytosed into animal cells through several routes, including clathrin-coated pits and vesicles, caveolae or pathways that do not depend on caveolae or clathrin [1], in particular clathrin-independent carriers (CLICs) [2] or related GPI-enriched endocytic compartments (GEECs) [3]. While different proteins are sorted into these differ- ent pathways, for example the transferrin receptor into clathrin-coated pits, a given receptor may also be inter- nalized via different pathways depending on whether it triggers a signaling response or is destined for lysosomes [4]. Nevertheless, all endocytic routes are thought to converge on conventional endosomes, including caveolae whose interactions with endosomes are regulated [5]. It is not clear why receptors that have been internalized via separate pathways would then meet again in early endo- somes. However, evidence supports the notion that early endosomes contain different subpopulations or different regions and membrane domains, which presumably con- trol the trafficking of signaling receptors [4,6]. While traveling along the endocytic pathway, these continue to signal when associated with specialized subpopulations or regions of endosomes [4,7]. This may explain how some growth factors can elicit a complex, sometimes diverse, response through waves of compartmentalized signaling that are spatially and temporally regulated. In early endosomes, housekeeping receptors are uncoupled from their ligands at the mildly acidic (pH 6.2) pH [8] and recycled back to the plasma membrane directly or indirectly via recycling endosome, while other molecules are routed toward the trans-Golgi network (TGN) [9,10]. By contrast, signaling receptors that need to be downregulated, including activated epidermal growth factor receptor (EGFR), are sorted by endosomal sorting complex required for transport (ESCRT) com- plexes and their accessory proteins, into membrane inva- ginations that form toward the early endosome lumen [7,11–13] — ESCRT and the accessory protein ALG-2 interacting protein X (Alix) are also involved in the release of a number of viruses, including HIV-1, at the plasma membrane and during abscission in cytokinesis [14–16]. Membrane invagination within early endosomes leads to the formation of a multivesicular endosome or ECV/MVB (endosomal carrier vesicle/multivesicular body; Figure 1). In turn, epidermal growth factor (EGF) itself may stimulate both ECV/MVB biogenesis and inward vesiculation [17]. Once formed, ECV/MVBs detach — or mature — from early endosomes, rapidly acidify to pH  5.5 and undergo microtubule-dependent transport toward late endosomes. These function as the last sorting station in the endocytic pathway from where protein and lipid, rather than being delivered to lyso- somes for degradation, can be retrieved and transported to other cellular destinations [18], including the TGN [19– 21] and the plasma membrane at least in some cell types [22,23  ]. Finally, late endosomes and lysosomes are also connected to the autophagy pathway [24]. Virus entry Different types of viruses have evolved different, some- times elaborate, strategies to adsorb onto, penetrate and infect mammalian cells, so that they can deliver their genomes for infection to proceed [25,26]. In addition, a given virus may exploit multiple cell surface receptors and cellular functions, including the triggering of sig- naling cascades to elicit its own penetration [26,27]. Some viruses may also enter cells by more than one route. For example, enveloped viruses such as HIV and many other retroviruses undergo fusion with the plasma membrane but are also endocytosed and thus can potentially infect cells from the cell surface and from endosomes. Another Current Opinion in Cell Biology 2009, 21:582–588 www.sciencedirect.com