Shaping the Endoplasmic Reticulum into a Social Network

doi:10.1016/j.tcb.2016.06.002

Trends in Cell Biology

Volume 26, Issue 12, December 2016, Pages 934-943

https://doi.org/10.1016/j.tcb.2016.06.002 Get rights and content

Trends

ER sheets and tubules are generated by membrane curvature stabilization, and tubules are fused into a reticular network by membrane-bound GTPases. Mechanistic studies reveal that transmembrane hairpins, amphipathic helices and coiled coils are important tools for ER morphogenesis.

The ER contacts other organelles at discrete sites, where lipid transfer and calcium exchange occur. Various aspects of organelle dynamics, including fission, maturation and positioning, are also regulated by formation of contacts with the ER. The morphology of the ER controls the shape and area of the contact with other organelles, and thus the function of contact sites.

Formation and maintenance of ER morphology are of general importance. When ER morphology is perturbed, organelle contacts, membrane trafficking and other ER functions are affected, and neurodegenerative diseases may result.

In eukaryotic cells, the endoplasmic reticulum (ER) is constructed as a network of tubules and sheets that exist in one continuous membrane system. Several classes of integral membrane protein have been shown to shape ER membranes. Functional studies using mutant proteins have begun to reveal the significance of ER morphology and membrane dynamics. In this review, we discuss the common protein modules and mechanisms that generate the characteristic shape of the ER. We also describe the cellular functions closely related to ER morphology, particularly contacts with other membrane systems, and their potential roles in the development of multicellular organisms.

Section snippets

Unique Morphology and Diverse Roles of the ER: A Perfect Model for Connecting Membrane Dynamics to Organellar Functions

The ER is a single membrane-bound organelle involved in many critical cellular processes, including protein synthesis, lipid synthesis, and calcium storage. Some organelles adopt globular shapes, but the ER consists of interconnected membrane tubules and sheets 1, 2. From the center of a cell, the ER starts as the outer nuclear membrane (ONM), which is the outer layer of the nuclear envelope (NE). Most of the ER sheets, which are cisternal structures with two closely apposed membranes, appear

Formation of ER Tubules

ER tubules are cylindrical structures with a diameter of ∼30 nm in yeast and ∼50 nm in mammals. Rtns were identified as ER tubule-forming proteins in an in vitro ER network formation assay using Xenopus membrane extracts [6]. Subsequent analysis uncovered a similar protein named REEP5/DP1 in mammals and Yop1p in yeast. Overexpression of these proteins results in more ER tubules, and deletion or depletion has the opposite effect. The role of Yop1p or Rtn1p in tubule formation was confirmed when

ER morphology in Membrane Contact Sites

To maintain cellular homeostasis, organelles are connected by vesicle-mediated trafficking and membrane contact sites (MCSs) at which two heterologous membranes are closely apposed (typically within 30 nm) but do not fuse. The ER forms MCSs with multiple membrane systems, including the plasma membrane (PM), mitochondria, Golgi, endosomes, and lipid droplets (LDs) (Figure 2). Association of the ER with other organelles generally involves protein–protein interactions and/or protein–phospholipid

ER Morphology in Membrane Trafficking

In addition to direct contacts, vesicle-based trafficking is a major pathway for exchanging materials between membrane systems. Newly synthesized proteins or lipids are packed into COPII-coated vesicles and leave the ER through ER exit sites (ERESs). Because the curvature of a vesicle is comparable to that of a tubule cross-section, COPII vesicles are speculated to be preferentially generated in ER tubules. ERESs are enriched in tubules [17]. Most ER tubules are peripherally localized, but a

ER Morphology in Multicellular Development

ER morphogenesis, especially tubular network formation, appears to be a highly conserved process in eukaryotes. ER shaping and remodeling are expected to play a fundamental role during development. Surprisingly, in the basic eukaryotic model, the growth of yeast cells is only slowed when Yop1p and Rtn1p are deleted, and sey1Δ cells seem to be normal [7]. The functions of these proteins could be fulfilled by yet unknown analogous proteins. ER membrane dynamics have also been suggested to be more

Concluding Remarks

The network of tubules and sheets in the ER are generated by shared mechanisms using common protein modules, such as TMHs, APHs, and CCs. Many functions of the ER, including organelle contacts, rely on its morphological features (see Outstanding Questions). Although ER sheets serve as a platform for protein synthesis, the tubular ER network provides advantages in membrane trafficking. Processes such as lipid synthesis, though not discussed here, also profoundly affect ER shaping 15, 65, and are

Acknowledgments

We are grateful to Drs. Isabel Hanson and Alicia Prater for editing the work and to Dr. Sha Sun for help with the figures. Dr. Hong Zhang was supported by grants from the National Natural Science Foundation of China (NSFC) (31421002, 31561143001, 31225018), the National Basic Research Program of China (2013CB910100), and an International Early Career Scientist grant from the Howard Hughes Medical Institute. J.H. is supported by the NSFC (31225006), the National Basic Research Program of China

Glossary

Amphipathic helix (APH): an α-helix with hydrophobic residues on one side and hydrophilic residues on the other side. These helices can insert shallowly into membranes, in some cases inducing curvature, and in other cases sensing it.
Coiled coil (CC): a structural motif in proteins where α-helices are intertwined. Hydrophobic residues are usually packed in the core of the coil, and repeated sequences are common. CCs are often involved in oligomerization and tethering.
ER-mitochondria encounter

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Unlike most other organelles found in multiple copies, the endoplasmic reticulum (ER) is a unique singular organelle within eukaryotic cells. Despite its continuous membrane structure, encompassing more than half of the cellular endomembrane system, the ER is subdivided into specialized sub-compartments, including morphological, membrane contact site (MCS), and de novo organelle biogenesis domains. In this review, we discuss recent emerging evidence indicating that, in response to nutrient stress, cells undergo a reorganization of these sub-compartmental ER domains through two main mechanisms: non-destructive remodeling of morphological ER domains via regulation of MCS and organelle hitchhiking, and destructive remodeling of specialized domains by ER-phagy. We further highlight and propose a critical role of membrane lipid metabolism in this ER remodeling during starvation.
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The endoplasmic reticulum (ER) consists of the nuclear envelope and a connected peripheral network of tubules and interspersed sheets. The structure of ER tubules is generated and maintained by various proteins, including reticulons, DP1/Yop1p, atlastins, and lunapark. Reticulons and DP1/Yop1p stabilize the high membrane curvature of ER tubules, and atlastins mediate homotypic membrane fusion between ER tubules; however, the exact role of lunapark remains poorly characterized. Here, using isolated yeast ER microsomes and reconstituted proteoliposomes, we directly examined the function of the yeast lunapark Lnp1p for yeast atlastin Sey1p-mediated ER fusion and found that Lnp1p inhibits Sey1p-driven membrane fusion. Furthermore, by using a newly developed assay for monitoring trans-Sey1p complex assembly, a prerequisite for ER fusion, we found that assembly of trans-Sey1p complexes was increased by the deletion of LNP1 and decreased by the overexpression of Lnp1p, indicating that Lnp1p inhibits Sey1p-mediated fusion by interfering with assembly of trans-Sey1p complexes.
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Organelles perform critical biological functions due to their distinct molecular composition and internal environment. Disorders in organelles or their interacting networks have been linked to the incidence of numerous diseases, and the research of pharmacological actions at the organelle level has sparked pharmacists' interest. Currently, cell imaging has evolved into a critical tool for drug delivery, drug discovery, and pharmacological research. The introduction of advanced imaging techniques in recent years has provided researchers with richer biological information for viewing and studying the ultrastructure of organelles, protein interactions, and gene transcription activities, leading to the design and delivery of precision-targeted drugs. Therefore, this reviews the research on organelles-targeted drugs based upon imaging technologies and development of fluorescent molecules for medicinal purposes. We also give a thorough analysis of a number of subcellular-level elements of drug development, including subcellular research instruments and methods, organelle biological event investigation, subcellular target and drug identification, and design of subcellular delivery systems. This review will make it possible to promote drug research from the individual/cellular level to the subcellular level, as well as give a new focus based on newly found organelle activities.
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Trends in Cell Biology

ReviewShaping the Endoplasmic Reticulum into a Social Network

Trends

Section snippets

Unique Morphology and Diverse Roles of the ER: A Perfect Model for Connecting Membrane Dynamics to Organellar Functions

Formation of ER Tubules

ER morphology in Membrane Contact Sites

ER Morphology in Membrane Trafficking

ER Morphology in Multicellular Development

Concluding Remarks

Acknowledgments

Glossary

Int. Rev. Cytol.

Cell

Cell

Cell

Cell

J. Biol. Chem.

J. Biol. Chem.

Cell

Dev. Cell

J. Biol. Chem.

Dev. Biol.

Trends Cell Biol.

Dev. Cell

Curr. Opin. Cell Biol.

Cell

Cell

Cell Rep.

Mol. Cell. Neurosci.

Lancet Neurol.

Mechanisms shaping the membranes of cellular organelles

Annu. Rev. Cell Dev. Biol.

A 3D analysis of yeast ER structure reveals how ER domains are organized by membrane curvature

J. Cell Biol.

From myofibril to membrane; the transitional junction at the intercalated disc

Front. Biosci.

Homotypic fusion of ER membranes requires the dynamin-like GTPase atlastin

Nature

ER network formation requires a balance of the dynamin-like GTPase Sey1p and the Lunapark family member Lnp1p

Nat. Cell Biol.

A model for the generation and interconversion of ER morphologies

Proc. Natl. Acad. Sci. U.S.A.

Lunapark stabilizes nascent three-way junctions in the endoplasmic reticulum

Proc. Natl. Acad. Sci. U.S.A.

Protrudin binds atlastins and endoplasmic reticulum-shaping proteins and regulates network formation

Proc. Natl. Acad. Sci. U.S.A.

Rab10 GTPase regulates ER dynamics and morphology

Nat. Cell Biol.

Rab18 and a Rab18 GEF complex are required for normal ER structure

J. Cell Biol.

High-curvature domains of the ER are important for the organization of ER exit sites in Saccharomyces cerevisiae

J. Cell Sci.

Membrane proteins of the endoplasmic reticulum induce high-curvature tubules

Science

Arl6IP1 has the ability to shape the mammalian ER membrane in a reticulon-like fashion

Biochem. J.

Regulation of endoplasmic reticulum turnover by selective autophagy

Nature

A conserved amphipathic helix is required for membrane tubule formation by Yop1p

Proc. Natl. Acad. Sci. U.S.A.

Form follows function: the importance of endoplasmic reticulum shape

Annu. Rev. Biochem.

Subdomain-specific localization of CLIMP-63 (p63) in the endoplasmic reticulum is mediated by its luminal alpha-helical segment

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Interactions between nuclei and the cytoskeleton are mediated by SUN-KASH nuclear-envelope bridges

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Accessorizing and anchoring the LINC complex for multifunctionality

J. Cell Biol.

The dynamin-like GTPase Sey1p mediates homotypic ER fusion in S. cerevisiae

J. Cell Biol.

ROOT HAIR DEFECTIVE3 family of dynamin-like GTPases mediates homotypic endoplasmic reticulum fusion and is essential for Arabidopsis development

Plant Physiol.

Review
Shaping the Endoplasmic Reticulum into a Social Network