Review
Vesicle-mediated ER export of proteins and lipids

https://doi.org/10.1016/j.bbalip.2012.01.005Get rights and content

Abstract

In eukaryotic cells, the endoplasmic reticulum (ER) is a major site of synthesis of both lipids and proteins, many of which must be transported to other organelles. The COPII coat—comprising Sar1, Sec23/24, Sec13/31—generates transport vesicles that mediate the bulk of protein/lipid export from the ER. The coat exhibits remarkable flexibility in its ability to specifically select and accommodate a large number of cargoes with diverse properties. In this review, we discuss the fundamentals of COPII vesicle production and describe recent advances that further our understanding of just how flexible COPII cargo recruitment and vesicle formation may be. Large or bulky cargo molecules (e.g. collagen rods and lipoprotein particles) exceed the canonical size for COPII vesicles and seem to rely on the additional action of recently identified accessory molecules. Although the bulk of the research has focused on the fate of protein cargo, the mechanisms and regulation of lipid transport are equally critical to cellular survival. From their site of synthesis in the ER, phospholipids, sphingolipids and sterols exit the ER, either accompanying cargo in vesicles or directly across the cytoplasm shielded by lipid-transfer proteins. Finally, we highlight the current challenges to the field in addressing the physiological regulation of COPII vesicle production and the molecular details of how diverse cargoes, both proteins and lipids, are accommodated. This article is part of a Special Issue entitled Lipids and Vesicular Transport.

Highlights

► Transport of lipids and proteins from the ER is a highly regulated process. ► Protein exit from the ER occurs via signal-mediate export and bulk flow. ► The COPII machinery can adapt to export large or bulky cargoes. ► ER export of lipids occurs via both vesicular and non-vesicular mechanisms.

Section snippets

Introduction: the COPII coat marks the way out

The ER is a remarkably productive organelle, being the site of secretory protein synthesis and a major source of intracellular lipid synthesis. Furthermore, it maintains a highly dynamic structure, comprising the nuclear envelope, membrane sheets, tubules and cisternae that are fully interconnected [1], [2], [3]. To maintain this structure and functionality requires tight regulation of a number of processes including protein and lipid transport. Within the spectrum of diverse eukaryotic cells,

ER export of protein cargo

The process of accurate and selective recruitment of cargo proteins into nascent COPII vesicles is an integral part of the fidelity of ER export and transport through the secretory pathway. Indeed, the sheer volume and diversity of molecules that traffic through the ER is a testament to the flexibility of this process: it is estimated up to one-third of all proteins in yeast, ~ 70% of hepatocyte proteins and ~ 6000 proteins in human cells traffic through the ER for secretion or delivery to other

Lipid traffic from the ER

Although primarily studied for its role in the synthesis of secretory proteins, the ER is also central to endomembrane homeostasis as a key site of lipid synthesis. Over 1000 different lipid species comprise cellular membranes [105], forming three major groups based on their chemical structures—glycerophospholipids, sterols and sphingolipids. The distribution of these lipids varies within the cell, with different intracellular compartments enclosed by membranes with distinct compositions with

Conclusions and perspectives

New challenges are now emerging in understanding export from the ER. The minimal components of canonical COPII vesicle formation have been characterized extensively, and recent efforts are focusing on not only the flexibility of the COPII machinery but also how this machinery is coordinated in vivo. While recapitulating the minimal COPII machinery in vitro can describe the molecular detail of vesicle formation, it cannot report on any diversity in the vesicles formed in the cell. For example,

Acknowledgement

Work in the Miller lab is supported by NIH grants GM085089 and GM078186.

References (141)

  • A. Blumental-Perry et al.

    Phosphatidylinositol 4-phosphate formation at ER exit sites regulates ER export

    Dev. Cell

    (2006)
  • M. Muñiz et al.

    Protein sorting upon exit from the endoplasmic reticulum

    Cell

    (2001)
  • R. Peng et al.

    Evidence for overlapping and distinct functions in protein transport of coat protein Sec24p family members

    J. Biol. Chem.

    (2000)
  • D.A. Shaywitz et al.

    COPII subunit interactions in the assembly of the vesicle coat

    J. Biol. Chem.

    (1997)
  • E.A. Miller et al.

    Regulation of coat assembly—sorting things out at the ER

    Curr. Opin. Cell Biol.

    (2010)
  • E.A. Miller et al.

    Multiple cargo binding sites on the COPII subunit Sec24p ensure capture of diverse membrane proteins into transport vesicles

    Cell

    (2003)
  • E. Mossessova et al.

    SNARE selectivity of the COPII coat

    Cell

    (2003)
  • F. Kappeler et al.

    The recycling of ERGIC-53 in the early secretory pathway. ERGIC-53 carries a cytosolic endoplasmic reticulum-exit determinant interacting with COPII

    J. Biol. Chem.

    (1997)
  • S. Sucic et al.

    The serotonin transporter is an exclusive client of the COPII component SEC24C

    J. Biol. Chem.

    (2011)
  • W.C. Nichols et al.

    From the ER to the golgi: insights from the study of combined factors V and VIII deficiency

    Am. J. Hum. Genet.

    (1999)
  • K. Saito et al.

    TANGO1 facilitates cargo loading at endoplasmic reticulum exit sites

    Cell

    (2009)
  • M.C.S. Lee et al.

    Ceramide biosynthesis is required for the formation of the oligomeric H+-ATPase Pma1p in the yeast endoplasmic reticulum

    J. Biol. Chem.

    (2002)
  • M. Fujita et al.

    Structural remodeling of GPI anchors during biosynthesis and after attachment to proteins

    FEBS Lett.

    (2010)
  • D.A. Brown et al.

    Sorting of GPI-anchored proteins to glycolipid-enriched membrane subdomains during transport to the apical cell surface

    Cell

    (1992)
  • R. Watanabe et al.

    Sphingolipids are required for the stable membrane association of glycosylphosphatidylinositol-anchored proteins in yeast

    J. Biol. Chem.

    (2002)
  • W.J. Belden et al.

    Distinct roles for the cytoplasmic tail sequences of Emp24p and Erv25p in transport between the endoplasmic reticulum and Golgi complex

    J. Biol. Chem.

    (2001)
  • W.J. Belden et al.

    Erv25p, a component of COPII-coated vesicles, forms a complex with Emp24p that is required for efficient endoplasmic reticulum to Golgi transport

    J. Biol. Chem.

    (1996)
  • M. Fujita et al.

    GPI glycan remodeling by PGAP5 regulates transport of GPI-anchored proteins from the ER to the Golgi

    Cell

    (2009)
  • S.M. Stagg et al.

    Structural basis for cargo regulation of COPII coat assembly

    Cell

    (2008)
  • F.T. Wieland et al.

    The rate of bulk flow from the endoplasmic reticulum to the cell surface

    Cell

    (1987)
  • S.I. Bannykh et al.

    Membrane dynamics at the endoplasmic reticulum–Golgi interface

    J. Cell Biol.

    (1997)
  • G. Palade

    Intracellular aspects of the process of protein synthesis

    Science

    (1975)
  • M.C.S. Lee et al.

    Bi-directional protein transport between the ER and Golgi

    Annu. Rev. Cell Dev. Biol.

    (2004)
  • S.A. Boyadjiev et al.

    Cranio-lenticulo-sutural dysplasia is caused by a SEC23A mutation leading to abnormal endoplasmic-reticulum-to-Golgi trafficking

    Nat. Genet.

    (2006)
  • B. Jones et al.

    Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders

    Nat. Genet.

    (2003)
  • K. Schwarz et al.

    Mutations affecting the secretory COPII coat component SEC23B cause congenital dyserythropoietic anemia type II

    Nat. Genet.

    (2009)
  • P. Bianchi et al.

    Congenital dyserythropoietic anemia type II (CDAII) is caused by mutations in the SEC23B gene

    Hum. Mutat.

    (2009)
  • M. Huang et al.

    Crystal structure of Sar1-GDP at 1.7 A resolution and the role of the NH2 terminus in ER export

    J. Cell Biol.

    (2001)
  • X. Bi et al.

    Structure of the Sec23/24-Sar1 pre-budding complex of the COPII vesicle coat

    Nature

    (2002)
  • M. Aridor et al.

    The Sar1 GTPase coordinates biosynthetic cargo selection with endoplasmic reticulum export site assembly

    J. Cell Biol.

    (2001)
  • A. Bielli et al.

    Regulation of Sar1 NH2 terminus by GTP binding and hydrolysis promotes membrane deformation to control COPII vesicle fission

    J. Cell Biol.

    (2005)
  • T. Yoshihisa et al.

    Requirement for a GTPase-activating protein in vesicle budding from the endoplasmic reticulum

    Science

    (1993)
  • C. Russell et al.

    New insights into the structural mechanisms of the COPII coat

    Traffic

    (2009)
  • B. Antonny et al.

    Dynamics of the COPII coat with GTP and stable analogues

    Nat. Cell Biol.

    (2001)
  • E. Futai et al.

    GTP/GDP exchange by Sec12p enables COPII vesicle bud formation on synthetic liposomes

    EMBO J.

    (2004)
  • K. Sato et al.

    Dissection of COPII subunit-cargo assembly and disassembly kinetics during Sar1p-GTP hydrolysis

    Nat. Struct. Mol. Biol.

    (2005)
  • H. Cai et al.

    TRAPPI tethers COPII vesicles by binding the coat subunit Sec23

    Nature

    (2007)
  • C. Lord et al.

    Sequential interactions with Sec23 control the direction of vesicle traffic

    Nature

    (2011)
  • K. Tabata et al.

    Visualization of cargo concentration by COPII minimal machinery in a planar lipid membrane

    EMBO J.

    (2009)
  • F. Supek et al.

    Sec16p potentiates the action of COPII proteins to bud transport vesicles

    J. Cell Biol.

    (2002)
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    This article is part of a Special Issue entitled Lipids and Vesicular Transport.

    1

    These authors contributed equally.

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