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

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.

Abstract

The ADP-ribosylation factor (ARF) and ARF-like (ARL) family of G proteins, which are known to regulate membrane traffic and organelle structure, are emerging as regulators of diverse processes, including lipid and cytoskeletal transport. Although traditionally viewed as part of a linear signalling pathway, ARFs and their regulators must now be considered to exist within functional networks, in which both the 'inactive' ARF and the regulators themselves can mediate distinct effects.

Abstract

Members of the ADP-ribosylation factor (ARF) family of guanine-nucleotide-binding (G) proteins, including the ARF-like (ARL) proteins and SAR1, regulate membrane traffic and organelle structure by recruiting cargo-sorting coat proteins, modulating membrane lipid composition, and interacting with regulators of other G proteins. New roles of ARF and ARL proteins are emerging, including novel functions at the Golgi complex and in cilia formation. Their function is under tight spatial control, which is mediated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) that catalyse GTP exchange and hydrolysis, respectively. Important advances are being gained in our understanding of the functional networks that are formed not only by the GEFs and GAPs themselves but also by the inactive forms of the ARF proteins.