Regulation of vesicle trafficking: GTPases and friends.

With the 2013 Nobel Prize awarded to scientists who uncovered mechanisms of vesicular trafficking, the next big question in the field is how this process is regulated. Talks in the Minisymposium on “Regulation of Vesicle Trafficking” highlighted ways in which GTPases from the highly conserved Ypt/Rab and Arf families regulate and coordinate vesicle trafficking steps. The roles of luminal phosphorylation and calcium signaling in this process were also underlined (see Figure 1). FIGURE 1: Regulation of vesicle trafficking. Vesicles carrying luminal or membrane protein cargo (blue) are formed on one compartment and fuse with the next. Regulation processes discussed here are shown at the top (see the text for details). Vesicular trafficking ... How do downstream effectors of GTPases mediate transport steps? When stimulated, GTPases recruit their effectors to mediate the various steps of vesicular transport. Three talks described how these effectors function. Bruno Goud (Institut Curie) talked about two molecular motors, an actin-based myosin and a microtubule-based kinesin, that act as Rab6 effectors to drive membrane fission during vesicle formation. Michael Ailion (University of Washington) described the identification of two Rab2 effectors in a genetic screen for Caenorhabditis elegans mutants defective in the maturation of neuronal dense-core vesicles. These effectors are part of a complex that contains Rab2, at least three Rab2 effectors, and a Rab2 GTPase-activating protein, underscoring the importance of large multiprotein complexes in vesicular trafficking. Anne Spang (University of Basel) talked about another protein complex, Exomer, which acts as an Arf effector to traffic cargo from the trans-Golgi network (TGN) to the plasma membrane (PM). The interesting twist in this story is the suggestion that prion domain–dependent aggregation might serve as a reversible signal for stalling of cargo in a compartment. GTPases and coordination GTPases are in a perfect position not only to regulate individual transport steps but also to coordinate them. Two talks described how different GTPases that function sequentially in the same pathway coordinate successive vesicular transport steps. In such cascades, the effector of one GTPase acts as a guanine-nucleotide exchange factor (GEF) of the next GTPase. Wei Guo (University of Pennsylvania) described two mechanisms that regulate recycling endosome-to-PM transport involving the stimulation of the GEF activity of Rabin8 on Rab8 by Rab11 and ERK1/2 phosphorylation. Chris Fromme (Cornell University) talked about a Rab-Arf cascade in which two Rabs regulate the Arf-GEF Sec7 at the TGN. Whereas Ypt1 (Rab1) helps recruit Sec7 to the Golgi, Ypt31/32 (Rab11) stimulates its GEF activity on Arf to stimulate vesicle formation. In another talk, Nava Segev (University of Illinois at Chicago) described how one Rab GTPase functions in two different GEF-GTPase-effector modules to coordinate transport from one compartment to two different destinations. When stimulated by one GEF, Ypt1 (Rab1) recruits certain effectors to regulate endoplasmic reticulum (ER)-to-Golgi transport in the secretory pathway. When stimulated by another GEF, the same Ypt recruits an autophagy-specific effector to shuttle membranes loaded with excess or misfolded proteins from the ER for degradation in the lysosome. Calcium signaling Calcium is a known signal of regulated secretion. However, its role in constitutive vesicular trafficking has been elusive. Jared Helm (Hay Laboratory, University of Montana) suggested a mechanism for the dependence of ER-to-Golgi transport on luminal calcium. On localized release of calcium from the ER, the calcium-binding protein ALG-2 interacts with the COPII coat component Sec31. This interaction ensures assembly of a functional vesicle and/or proper timing of its uncoating.