Induction of membrane curvature by proteins involved in Golgi trafficking

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Abstract

The Golgi apparatus serves a key role in processing and sorting lipids and proteins for delivery to their final cellular destinations. Vesicle exit from the Golgi initiates with directional deformation of the lipid bilayer to produce a bulge. Several mechanisms have been described by which lipids and proteins can induce directional membrane curvature to promote vesicle budding. Here we review some of the mechanisms implicated in inducing membrane curvature at the Golgi to promote vesicular trafficking to various cellular destinations.

Introduction

Vesicle budding is a key step in the movement of proteins and lipids from one organelle to another. The initial formation of a vesicle bud depends on mechanisms that induce directional curvature of the lipid bilayer membrane. The trans Golgi is an important membrane compartment in the secretory pathway that functions in sorting proteins and lipids to their final cellular destinations. Vesicles exit from the Golgi on their way to various destinations, including the plasma membrane (PM), late endosomes or lysosomes, or back to the Golgi or the endoplasmic reticulum (ER). Different cargoes presumably follow different routes (although some cargoes may have several destinations). These diverse pathways of exit from the Golgi predict the existence of multiple mechanisms of vesicle budding from the Golgi. Indeed, many such mechanisms have been described. Here we review some of the proteins found at the trans Golgi reported to have the ability to induce membrane curvature, and thus, may act to help drive vesicle budding from the Golgi.

Section snippets

Mechanisms to induce membrane curvature

Membrane curvature can be achieved through many different mechanisms (Fig. 1), all with the common feature that they act to asymmetrically impart directional deformation of the lipid bilayer (Daumke et al., 2014; Hu et al., 2011; Jarsch et al., 2016; McMahon and Boucrot, 2015; Zimmerberg and Kozlov, 2006). For example, asymmetric insertion of lipids or proteins into one leaflet of the bilayer increases the surface area of one leaflet relative to the other, driving bilayer puckering to

Role of lipids to induce membrane curvature at the Golgi

At the Golgi, it has been proposed that the composition of the lipid bilayer may play a role in the process of vesicle budding for forward trafficking (Shemesh et al., 2003). While this model is understandably attractive, the data supporting it remain sparse. Rather, a large body of data supports the idea that effector proteins recruited by lipids play a dominant role in the process of vesicle budding at the Golgi.

The cytosolic leaflet of the trans Golgi is highly enriched in

ARF

The ADP-ribosylation factor (ARF) family proteins are small GTPases related to the well known COPII ER secretory protein, Sar1 (Kahn and Gilman, 1984, 1986; Lee et al., 2005; Sztul et al., 2019; Tan and Gleeson, 2019). The ARFs bind GTP/GDP under the influence of various ARF guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) (Sztul et al., 2019; Tan and Gleeson, 2019). ARFs are cytosolic proteins, but the GTP-loaded form preferentially binds to membrane via

Arfaptin

Arfaptins, as the name implies, are proteins that were identified to bind to ARF family proteins (Kanoh et al., 1997). However, they also exhibit comparable affinity for other small GTPases, such as Rac (Tarricone et al., 2001). Arfaptins-1 and -2 both localize to the Golgi (Kanoh et al., 1997). Notably, the structure of Arfaptins reveals the presence of a crescent-shaped BAR domain (Fig. 1B) (Peter et al., 2004; Tarricone et al., 2001). Arfaptins have been shown to induce tubulation of

Exomer

Exomer is a cargo adaptor complex found only in yeast, where it is required for trafficking a subset of specialized cargo, including Chs3p, Fus1p and Pin2p, directly from the late Golgi to the PM (Barfield et al., 2009; Guo et al., 2014; Paczkowski et al., 2015; Ritz et al., 2014; Sanchatjate and Schekman, 2006; Santos and Snyder, 2003, 1997; Trautwein et al., 2006; Wang et al., 2006). Exomer is composed of a homodimer of the core scaffolding subunit, Chs5p, and two of four cargo-binding

EpsinR

EpsinR (also known as CLINT1 or Enthoprotin) is an epsin family protein that localizes to the Golgi, and, like other epsin family members, contains an ENTH domain and interacts with AP family proteins, in this case, AP-1 (Ford et al., 2002; Hirst et al., 2003; Kalthoff et al., 2002; Mills et al., 2003; Wasiak et al., 2002). Other ENTH domains, for example from Epsin1, are well-known to induce membrane curvature in vitro and in cells via insertion of an amphipathic alpha helix into the proximal

Clathrin

Clathrin-coated vesicles are one of the major classes of transport vesicles, most thoroughly studied for their role in receptor-mediated endocytosis. However, clathrin is also observed at the Golgi and in vesicles that bud from the Golgi (Hinners and Tooze, 2003; Jaiswal et al., 2009). Several proteins that associate with the trans Golgi and are involved in vesicle budding interact directly or indirectly with clathrin. The AP and GGA family proteins are notable examples, and are discussed in

Adaptor proteins (APs)

AP complex proteins produce a family of multisubunit complexes that generally serve to link membranes to clathrin. While AP proteins themselves are not known to induce membrane curvature, they serve as a hub for interaction with other proteins that do. Five AP complexes have been identified and they all exhibit similar organization, consisting of two large subunits, a medium subunit, and a small subunit. However, they display differences in their cellular localization and mediate distinct

GGAs

Golgi-localized, γ-ear-containing, ARF-binding proteins (GGAs) are another family of proteins that are not known to directly impart membrane curvature, but recruit other proteins that do. Three GGAs are found in humans (GGA1, 2, and 3). Their association with the trans Golgi depends on PI4P along with an interaction with ARF1 (Dell’Angelica et al., 2000; Kametaka et al., 2010; Puertollano et al., 2001b; Wang et al., 2007). They further interact with APs, EpsinR, and clathrin, providing multiple

GOLPH3

GOLPH3 is an abundant peripheral membrane protein, highly localized to the trans Golgi and to vesicles budding from the trans Golgi (Bell et al., 2001; Dippold et al., 2009; Kuna and Field, 2019; Snyder et al., 2006; Wu et al., 2000). GOLPH3 binds tightly and specifically to PI4P both in vitro and in cells, which promotes GOLPH3 localization to the trans Golgi in humans and in S. cerevisiae (for the ortholog Vps74p) (Dippold et al., 2009). Upon binding to PI4P-containing membranes, GOLPH3

Conclusion

Many proteins have been implicated in driving vesicle exit from the Golgi, employing a variety of mechanisms to deform the membrane to initiate budding. Less clear are which cargoes and which trafficking routes to different destinations depend on which vesicle trafficking mechanisms. Approaches to systematically disentangle the relationships will be needed to more fully understand the secretory pathway.

Funding

This work was supported by NIH grants (R01 GM120055 and R01 CA201303), a Scholar-Innovator Award from the Harrington Discovery Institute, and an NCI Cancer Centers Council/Padres Pedal the Cause Award #PTC2019 for cancer research.

Declaration of Competing interest

We have no conflicts to report.

Acknowledgments

We thank members of the Field lab for critical reading of the manuscript. We thank the many people who have contributed to our understanding of the Golgi, and apologize for our space-limited citation list. Although we are unable to provide an exhaustive review, we hope to have provided a point of view for consideration of the literature.

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