The Arf family GTPases: Regulation of vesicle biogenesis and beyond

Abstract

The Arf family proteins are best known for their roles in the vesicle biogenesis. However, they also play fundamental roles in a wide range of cellular regulation besides vesicular trafficking, such as modulation of lipid metabolic enzymes, cytoskeleton remodeling, ciliogenesis, lysosomal, and mitochondrial morphology and functions. Growing studies continue to expand the downstream effector landscape of Arf proteins, especially for the less‐studied members, revealing new biological functions, such as amino acid sensing. Experiments with cutting‐edge technologies and in vivo functional studies in the last decade help to provide a more comprehensive view of Arf family functions. In this review, we summarize the cellular functions that are regulated by at least two different Arf members with an emphasis on those beyond vesicle biogenesis.

Arf family GTPases are present in Asgard archaea

“…The origin of the Arf family is less well understood, but it was already well-established in the last eukaryotic common ancestor (LECA), with 15 members present 23 . Arf family proteins, including classical Arfs as well as a plethora of Arf-like (Arl) proteins, Arfrp1 and Sar1, function in multiple steps of membrane trafficking including vesicle budding, movement of vesicles and organelles along cytoskeleton tracks, targeting and regulation of vesicle fusion, as well as in membrane lipid modification, lipid metabolism, cytoskeleton-membrane interaction and cilia transport [24][25][26] . Like other membrane-associated small GTPases in eukaryotes, Arf family proteins carry out their functions by recruiting effectors to the membrane in their active GTP-bound form 24,25,27 .…”

“…The crystal structures of numerous eukaryotic Arf family proteins have been solved, and all of them exhibit this characteristic conformational change between GDP-and GTP-bound forms [34][35][36][37][38][39] . Essentially all membrane trafficking routes within eukaryotic cells are regulated by at least one Arf family protein, and the wide range of functions of these GTPases allows vesicular trafficking to be coordinated with diverse cellular processes 25,27 . The origins of the Arf family GTPases, and the time of emergence of their hallmark mechanism of membrane localization, are currently unknown.…”

The ARF GTPase regulatory network in collective invasion and metastasis

“…Collectively, this demonstrates how alternate splicing of the lipid-interacting regions of ARF GEFs and GAPs can induce drastically different ARF module function outcome, by determining the microdomains at which these ARF modules can act. Importantly, ARFs can bind and stimulate the activity of both PI4-kinases and PI5-kinases [ 5 , 12 ], kinases that act sequentially in the production of PI(4,5)P 2 . This suggesting that ARFs are intimately linked to lipid metabolism, both producing and responding to distinct patterns of phosphoinositide production.…”