Abstract
Molecular switches of the ADP-ribosylation factor (ARF) GTPase family coordinate intracellular trafficking at all sorting stations along the secretory pathway, from the ER-Golgi-intermediate compartment (ERGIC) to the plasma membrane (PM). Their GDP-GTP switch is essential to trigger numerous processes, including membrane deformation, cargo sorting and recruitment of downstream coat proteins and effectors, such as lipid modifying enzymes. While ARFs (in particular ARF1) had mainly been studied in the context of coat protein recruitment at the Golgi, COPI/clathrin-independent roles have emerged in the last decade. Here we review the roles of human ARF1-5 GTPases in cellular trafficking with a particular emphasis on their roles in post-Golgi secretory trafficking and in sorting in the endo-lysosomal system.
Highlights
ADP-ribosylation factor GTPases are major regulators of intracellular trafficking
ADP-ribosylation factor (ARF) on/off switch is tightly regulated by guanine nucleotide exchange factors (GEFs), that turn ARFs on and GTPase activating proteins (GAPs), that trigger GTP hydrolysis, returning ARFs to the off state (Sztul et al, 2019)
This is the case of ARF6-GDP, which engages with regulators of other small G proteins, raising the interesting possibility that GDP and GTP bound ARF6 would lead to activation of alternate signaling pathways depending on the bound nucleotide [reviewed in Donaldson and Jackson (2011)]
Summary
ADP-ribosylation factor GTPases are major regulators of intracellular trafficking. Based on sequence similarities, they have been classified into type I (ARF1-3; humans lacking ARF2), type II (ARF4 and ARF5) and type III with the only member being the PM-localized ARF6. ARFs on/off switch is tightly regulated by guanine nucleotide exchange factors (GEFs), that turn ARFs on and GTPase activating proteins (GAPs), that trigger GTP hydrolysis, returning ARFs to the off state (Sztul et al, 2019). The ARF-GTP conformation is referred to as the “active” state, ARF proteins can interact with effectors in the “inactive” ARF-GDP bound state. This is the case of ARF6-GDP, which engages with regulators of other small G proteins, raising the interesting possibility that GDP and GTP bound ARF6 would lead to activation of alternate signaling pathways depending on the bound nucleotide [reviewed in Donaldson and Jackson (2011)]. A GTP-locked ARF6 mutant blocked membrane recycling between the PM and endosomes (Eyster et al, 2009) and the
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