Out of the ER—outfitters, escorts and guides

doi:10.1016/S0962-8924(98)01414-7

Trends in Cell Biology

Volume 9, Issue 1, 1 January 1999, Pages 5-7

https://doi.org/10.1016/S0962-8924(98)01414-7 Get rights and content

Abstract

The endoplasmic reticulum (ER) contains a variety of specialized proteins that interact with secretory proteins and facilitate their uptake into transport vesicles destined for the Golgi apparatus. These accessory proteins might induce and/or stabilize a conformation that is required for secretion competence or they might be directly involved in the sorting and uptake of secretory proteins into Golgi-bound vesicles. Recent efforts have aimed to identify and characterize the role of several of these substrate-specific accessory proteins.

Section snippets

Chaperones and folding catalysts

A screen for yeast mutants possessing a broad defect in amino acid uptake led to isolation of the SHR3 gene¹. Shr3p is a nonessential, ER-resident membrane protein that is specifically required for delivery of amino acid permeases to the plasma membrane. In wild-type cells, newly synthesized cargo proteins, including the general amino acid permease (Gap1p), have been found in association with the coat proteins (COPII) that form ER-to-Golgi transport vesicles (for review, see Ref. 2). In shr3

Transport receptors and guides

As described above, ‘transport receptors’ are accessory proteins that interact with specific secretory proteins in the donor compartment and then ‘guide’ them into appropriate transport vesicles. These receptors interact directly or indirectly with the coat proteins that form transport vesicles and thus serve as adaptors linking the vesicle-forming machinery to cargo recruitment. Examples of such adaptor molecules have been documented in the trans-Golgi compartment and on the plasma membrane,

Concluding remarks

In a few short years, we have come a long way from the notion of secretion being a default process. However, it is still too early to conclude that all soluble and membrane cargo proteins employ signals for their anterograde transport. A combination of genetic and biochemical analysis should facilitate the decoding of signals on cargo and adaptor proteins as well as the unravelling of the architecture of budding and secretion complexes in ER and vesicle membranes.

Acknowledgements

J.H. was supported by a fellowship from the Deutsche Forschungsgemeinschaft.

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The intracellular transport of lipophilic cargoes is a highly dynamic process. In eukaryotic cells, the uptake and release of long-chain fatty acids (LCFAs) are executed by fatty-acid binding proteins. However, how these carriers control the directionality of cargo trafficking remains unclear. Here, we revealed that the unliganded archetypal Drosophila brain-type fatty acid-binding protein (dFABP) possesses a stronger binding affinity than its liganded counterpart for empty nanodiscs (ND). Titrating unliganded dFABP and nanodiscs with LCFAs rescued the broadening of FABP cross-peak intensities in HSQC spectra from a weakened protein–membrane interaction. Two out of the 3 strongest LCFA contacting residues in dFABP identified by NMR HSQC chemical shift perturbation (CSP) are also part of the 30 ND-contacting residues (out of the total 130 residues in dFABP), revealed by attenuated TROSY signal in the presence of lipid ND to apo-like dFABP. Our crystallographic temperature factor data suggest enhanced αII helix dynamics upon LCFA binding, compensating for the entropic loss in the βC-D/βE-F loops. The aliphatic tail of bound LCFA impedes the charge-charge interaction between dFABP and the head groups of the membrane, and dFABP is prone to dissociate from the membrane upon ligand binding. We therefore conclude that lipophilic ligands participate directly in the control of the functionally required membrane association and dissociation of FABPs.
Proteostasis and "redoxtasis" in the secretory pathway: Tales of tails from ERp44 and immunoglobulins
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The bulk flow model states instead that all native proteins can exit from the ER at the same rate unless they are retained there. Velocity of secretion depends on folding efficiency [15–19]. The two models are not mutually exclusive, and evidence has been produced in favor of both: neither party can claim full victory.
In multicellular organisms, some cells are given the task of secreting huge quantities of proteins. To comply with their duty, they generally equip themselves with a highly developed endoplasmic reticulum (ER) and downstream organelles in the secretory pathway. These professional secretors face paramount proteostatic challenges in that they need to couple efficiency and fidelity in their secretory processes. On one hand, stringent quality control (QC) mechanisms operate from the ER onward to check the integrity of the secretome. On the other, the pressure to secrete can be overwhelming, as for instance on antibody-producing cells during infection. Maintaining homeostasis is particularly hard when the products to be released contain disulfide bonds, because oxidative folding entails production of reactive oxygen species. How are redox homeostasis (“redoxtasis”) and proteostasis maintained despite the massive fluxes of cargo proteins traversing the pathway? Here we describe recent findings on how ERp44, a multifunctional chaperone of the secretory pathway, can modulate these processes integrating protein QC, redoxtasis, and calcium signaling.
Sec24 is a coincidence detector that simultaneously binds two signals to drive ER export
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Incorporation of secretory proteins into ER-derived vesicles involves recognition of cytosolic signals by the COPII coat protein, Sec24. Additional cargo diversity is achieved through cargo receptors, which include the Erv14/Cornichon family that mediates export of transmembrane proteins despite the potential for such clients to directly interact with Sec24. The molecular function of Erv14 thus remains unclear, with possible roles in COPII binding, membrane domain chaperoning, and lipid organization.
Using a targeted mutagenesis approach to define the mechanism of Erv14 function, we identify conserved residues in the second transmembrane domain of Erv14 that mediate interaction with a subset of Erv14 clients. We further show that interaction of Erv14 with a novel cargo-binding surface on Sec24 is necessary for efficient trafficking of all of its clients. However, we also determine that some Erv14 clients also directly engage an adjacent cargo-binding domain of Sec24, suggesting a novel mode of dual interaction between cargo and coat.
We conclude that Erv14 functions as a canonical cargo receptor that couples membrane proteins to the COPII coat, but that maximal export requires a bivalent signal that derives from motifs on both the cargo protein and Erv14. Sec24 can thus be considered a coincidence detector that binds simultaneously to multiple signals to drive packaging of polytopic membrane proteins. This mode of dual signal binding to a single coat protein might serve as a general mechanism to trigger efficient capture, or may be specifically employed in ER export to control deployment of nascent proteins.
Protein Quality Control, Retention, and Degradation at the Endoplasmic Reticulum
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Shifting to the permissive temperature caused a rapid recruitment of the folded ts045 VSV-G to ERES, suggesting that access of this cargo to these specialized sites of ER export is regulated according to its folding state (Lee et al., 2004a; Mezzacasa and Helenius, 2002). The recruitment of cargo proteins to the COPII-coated buds is believed to be signal mediated (Herrmann et al., 1999; Kuehn et al., 1998; Nishimura and Balch, 1997), but non-selective incorporation by bulk flow might also exist for certain cargo proteins (Martinez-Menarguez et al., 1999; Wieland et al., 1987). Cargo proteins that are actively concentrated in the COPII-coated vesicle could bind the coat components either directly through their cytosolic domain, as in the case of most TM cargo proteins (Aridor et al., 1998; Kuehn et al., 1998; Votsmeier and Gallwitz, 2001) or indirectly, mediated by specific cargo TM receptors.
In order to maintain proper cellular functions, all living cells, from bacteria to mammalian cells, must carry out a rigorous quality control process in which nascent and newly synthesized proteins are examined. An important role of this process is to protect cells against pathological accumulation of unfolded and misfolded proteins. The endoplasmic reticulum (ER) has evolved as a staging ground for secretory protein synthesis with distinct sites for entry, quality control, and exit. In the ER, most proteins are N-glycosylated, a posttranslational modification that defines the quality control pathway that the protein will undergo. The folding state of glycoproteins is revealed by specific modifications of their N-glycans. Regardless of size and posttranslational modifications, the folding states of all proteins must be identified as unfolded, properly folded, or terminally misfolded and accordingly subjected to ER retention and continued folding attempts, export and maturation, or retrotranslocation to the cytosol for degradation. These processes involve specialized machineries that utilize molecular chaperones, protein- and N-glycan-modifying enzymes, and lectins for protein folding and quality control and ubiquitination and degradation machineries for disposal. All these machineries are regulated by a signaling pathway, the unfolded protein response, which upregulates ER functions when under the stress of high protein load. Here, we describe the molecular mechanisms that are implicated and discuss recent data that underline the importance of compartmentalization in the segregation of the various functions of the ER for their correct function.
Escorts take the lead: Molecular chaperones as therapeutic targets
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The functional and physiological diversity of transmembrane receptors results from factors that influence the pharmacology, signaling, and trafficking of these receptors. Receptor mutations and other modifications may lead to misfolding, intracellular retention, and ineffective signaling of transmembrane receptors. The importance of such mutations is highlighted by the fact that various diseases have been linked to mutations that lead to ineffective signaling of these receptors, resulting from the retention of receptors in intracellular compartments. Studies focused on understanding the regulation of trafficking and cell surface expression of newly synthesized receptors have highlighted molecular chaperones as key regulators of receptor maturation and sorting. In this chapter, we discuss the functions of molecular chaperones in the regulation of seven-transmembrane-containing G-protein-coupled receptor function and trafficking and explore ways in which chaperones can serve as novel therapeutic targets.
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Citation Excerpt :
Newly synthesized secretory proteins exit the endoplasmic reticulum (ER) in so-called COPII-coated vesicles (Bonifacino and Glick, 2004; Lee et al., 2004). A large number of proteins are required for the biogenesis of these vesicles, including chaperones and enzymes that fold the newly synthesized protein in the lumen of the ER, receptors that bind secretory cargo and help their recruitment into the newly forming carriers, structural coat proteins that help mold the flat ER membrane into a bud and promote its growth into a vesicular element, and components that catalyze the budding of cargo-loaded carriers from the ER (Herrmann et al., 1999; Lee et al., 2004). COPII coat-mediated budding of vesicles from the ER is relatively well characterized.
A genome-wide screen revealed previously unidentified components required for transport and Golgi organization (TANGO). We now provide evidence that one of these proteins, TANGO1, is an integral membrane protein localized to endoplasmic reticulum (ER) exit sites, with a luminal SH3 domain and a cytoplasmic proline-rich domain (PRD). Knockdown of TANGO1 inhibits export of bulky collagen VII from the ER. The SH3 domain of TANGO1 binds to collagen VII; the PRD binds to the COPII coat subunits, Sec23/24. In this scenario, PRD binding to Sec23/24 subunits could stall COPII carrier biogenesis to permit the luminal domain of TANGO1 to guide SH3-bound cargo into a growing carrier. All cells except those of hematopoietic origin express TANGO1. We propose that TANGO1 exports other cargoes in cells that do not secrete collagen VII. However, TANGO1 does not enter the budding carrier, which represents a unique mechanism to load cargo into COPII carriers.

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Trends in Cell Biology

ForumOut of the ER—outfitters, escorts and guides

Abstract

Section snippets

Chaperones and folding catalysts

Transport receptors and guides

Concluding remarks

Acknowledgements

Cell

Curr. Opin. Cell Biol.

Trends Biochem. Sci.

Trends Biochem. Sci.

Cell

Cell

Trends Cell Biol.

Curr. Opin. Cell Biol.

Curr. Opin. Cell Biol.

Gene

J. Biol. Chem.

Cell

J. Cell Biol.

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Out of the ER—outfitters, escorts and guides