ARF family G proteins and their regulators: roles in membrane transport, development and disease

Abstract

Key Points The ADP-ribosylation factor (ARF) family of guanine-nucleotide-binding (G) proteins, including the ARF proteins, ARF-like (ARL) proteins and SAR1, regulates membrane traffic and organelle structure, and each family member is regulated through a cycle of GTP binding and GTP hydrolysis, which activate and inactivate, respectively, the G protein. Traditionally, ARFs have been characterized for their immediate effects in the recruitment of coat proteins to drive cargo sorting, the recruitment of enzymes that can alter membrane lipid composition and the regulation of cytoskeletal factors. Now, new roles for ARFs have been discovered at the Golgi complex, for example in driving lipid transport. ARL proteins are also being increasingly linked to coordination of trafficking with cytoskeletal processes, for example during ciliogenesis. There is particular interest in the mechanisms that control recruitment of the ARF guanine nucleotide exchange factors (GEFs) that mediate GTP binding to ARFs and, in the case of the cytohesin (also known as ARNO) GEF, membrane recruitment is coupled to relief of autoinhibition. GEFs such as cytohesin may also participate in a cascade of activation between particular pairs of ARFs. Traditionally, G protein signalling has been viewed as a linear pathway, with the GDP-bound form of an ARF protein being inactive; however, more recent studies have highlighted novel roles for these GDP-bound forms and have also shown that GEFs and GTPase-activating proteins (GAPs) themselves can engage in distinct signalling responses through scaffolding functions.

The Drosophila Arf1 homologue Arf79F is essential for lamellipodium formation

“…Arf GTPases are best known for their roles in membrane trafficking and organelle organisation (Donaldson and Jackson, 2011) but they have also been implicated in actin-dependent processes at the plasma membrane (Boulay et al, 2008;Cohen et al, 2007;Myers and Casanova, 2008;Stalder et al, 2011). Here, we establish that Arf79F not only localises at the cell edge with the WRC component Sra1 but is also essential for lamellipodium formation.…”

“…In human cells, paralogous genes give rise to SCAR/WAVE1, WAVE2 and WAVE3, Sra1 and PIR121, and Abi1 and Abi2 to generate divergent WRC combinations. The mammalian Arf GTPase family is also divergent and can be divided into three subfamilies: Class 1 (Arf1, Arf3), Class 2 (Arf4, Arf5) and Class 3 (Arf6) (Donaldson and Jackson, 2011), which display significant functional redundancy (Volpicelli-Daley et al, 2005). In Drosophila cells however, each Arf class is represented by a single isoform, namely Arf79F (Class 1), Arf102F (Class 2) and Arf51F (Class 3).…”

“…1A,B) where they are best characterised as having roles in membrane trafficking and Golgi organisation (Donaldson and Jackson, 2011). We therefore addressed whether it is Arf79F-mediated membrane trafficking from the Golgi that is imperative for lamellipodia by examining the Golgi apparatus in Arf79F-silenced cells (Fig.…”

“…BFA eliminated lamellipodia and Sra1 at the cell cortex in ,84% of cells. Differences in effectiveness between inhibitors is probably due to their mechanism where SecinH3 targets the cytohesin-family of Arf GTPase activators, Steppke in Drosophila (Donaldson and Jackson, 2011;Fuss et al, 2006;Hafner et al, 2006), while BFA forms a ternary complex with Arf1-GDP and Arf GEFs that would sequester class 1 Arf GTPase(s) (Mossessova et al, 2003). To dissect whether the reduction in Sra1 localisation ensues directly from inhibiting Arf or indirectly as a consequence of inhibiting lamellipodia, we uncoupled the two with the actin polymerisation inhibitors latrunculin B (LatB) and cytochalasin (Fig.…”

A nonsense variant in HERC1 is associated with intellectual disability, megalencephaly, thick corpus callosum and cerebellar atrophy

“…Indeed, the N-terminus RLD1 domain acts as a GEF guanine nucleotide exchange factor (GEF) for small GTPases and can stimulate guanine nucleotide dissociation from ARF1 and ARF6 GTPases. 12 The ARF proteins are master mediators of membrane trafficking and vesicular transport; 16 misregulation of the ARF proteins causes not only lysosomal-related disorders 17 but also ID as seen in IQSEC2 patients in whom loss of IQSEC2 protein impairs ARF6 activation. 18 It is thus likely that the pathological mechanism underlying the loss of HERC1 involves several pathways, all of which have significant roles in early brain development and function.…”