Ypt/Rab GTPases: Principles learned from yeast

Abstract

Ypt/Rab GTPases are key regulators of all membrane trafficking events in eukaryotic cells. They act as molecular switches that attach to membranes via lipid tails to recruit their multiple downstream effectors, which mediate vesicular transport. Originally discovered in yeast as Ypts, they were later shown to be conserved from yeast to humans, where Rabs are relevant to a wide array of diseases. Major principles learned from our past studies in yeast are currently accepted in the Ypt/Rab field including: i) Ypt/Rabs are not transport-step specific, but are rather compartment specific, ii) stimulation by nucleotide exchangers, GEFs, is critical to their function, whereas GTP hydrolysis plays a role in their cycling between membranes and the cytoplasm for multiple rounds of action, iii) they mediate diverse functions ranging from vesicle formation to vesicle fusion, and iv) they act in GTPase cascades to regulate intracellular trafficking pathways. Our recent studies on Ypt1 and Ypt31/Ypt32 and their modular GEF complex TRAPP raise three exciting novel paradigms for Ypt/Rab function: (a) coordination of vesicular transport substeps, (b) integration of individual transport steps into pathways, and (c) coordination of different transport pathways. In addition to its amenability to genetic analysis, yeast provides a superior model system for future studies on the role of Ypt/Rabs in traffic coordination due to the smaller proteome that results in a simpler traffic grid. We propose that different types of coordination are important also in human cells for fine-tuning of intracellular trafficking, and that coordination defects could result in disease.

Regulation of Golgi Cisternal Progression by Ypt/Rab GTPases

“…Thus, our and others cumulative data reinforce the idea that TRAPP I-stimulated Ypt1 regulates transport at the early Golgi, whereas TRAPP II-activated Ypt31/32 regulate transport at the late Golgi. This placement agrees with the established roles of Ypt1 and Ypt31 on the two sides of the Golgi (Lipatova et al, 2015). It also supports the idea that although Ypt/Rab GTPases can regulate multiple transport steps (Lipatova and Segev, 2014), they are specific to intracellular compartments (Zerial and McBride, 2001).…”

“…Based on our cumulative data, we proposed that TRAPP I acts as the GEF for Ypt1 to regulate ER-to-Golgi traffic and TRAPP II stimulates Ypt31/32 to mediate traffic at the trans Golgi (Lipatova et al, 2015). However, based on ~60% co-localization of mCherry-tagged Ypt1 with Sec7, which is considered a late-Golgi marker (Sclafani et al, 2010; Suda et al, 2013), assignment of a role for Ypt1 in late Golgi (Sclafani et al, 2010), and different specificity of GEF activity assays (Cai et al, 2008), a different view exists in the field.…”

Ypt/Rab GTPases and their TRAPP GEFs at the Golgi

“…This plasticity probably requires different GEFs in addition to different effectors. We have proposed that Ypt/Rabs function in GEF‐GTPase‐effector modules, which are specific to individual transport steps and/or pathways .…”

A Steric Gating Mechanism Dictates the Substrate Specificity of a Rab-GEF

“…In yeast the Rab GTPases Ypt1 (Rab1) and Ypt31/32 (Rab11) regulate trafficking in the secretory, endocytic, and autophagic pathways (Lipatova et al, 2015). These Rabs are activated by the related multi-subunit TRAPP complexes, TRAPPII and TRAPPIII.…”