Mutations in the ER–Golgi Intermediate Compartment Protein ERGIC-53 Cause Combined Deficiency of Coagulation Factors V and VIII

Nichols, William C.; Seligsohn, Uri; Zivelin, Ariella; Terry, Valeri H.; Hertel, Colette E.; Wheatley, Matthew; Moussalli, Micheline J.; Hauri, Hans Peter; Ciavarella, N.; Kaufman, Randal J.; Ginsburg, David

doi:10.1016/s0092-8674(00)81146-0

Cited by 427 publications

(337 citation statements)

References 56 publications

(21 reference statements)

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“…Once ALP reaches Golgi compartments, AP3-dependent delivery to the vacuole (Piper et al, 1997;Cowles et al, 1997;Vowels and Payne, 1998) and Pep4p-dependent maturation (Klionsky and Emr, 1989) seem to proceed at wildtype rates. Similar reductions in the transport rate of soluble secretory cargo have been observed in the absence of other specific ER cargo receptors, including Erv29p-dependent export of yeast gp␣f and CPY ) as well as the ERGIC53-dependent export of coagulation factors V/VII and procathepsin Z in animal cells (Nichols et al, 1998;Appenzeller et al, 1999). Some type I integral membrane cargo are also known to depend on cycling cargo receptors such as Erv14p (Powers and Barlowe, 1998), Emp47p (Sato and Nakano, 2003), and Vma21p (Malkus et al, 2004) for ER export.…”

Section: Discussionmentioning

confidence: 60%

Erv26p Directs Pro-Alkaline Phosphatase into Endoplasmic Reticulum–derived Coat Protein Complex II Transport Vesicles

Bue

Bentivoglio

Barlowe

2006

MBoC

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Secretory proteins are exported from the endoplasmic reticulum (ER) in transport vesicles formed by the coat protein complex II (COPII). We detected Erv26p as an integral membrane protein that was efficiently packaged into COPII vesicles and cycled between the ER and Golgi compartments. The erv26⌬ mutant displayed a selective secretory defect in which the pro-form of vacuolar alkaline phosphatase (pro-ALP) accumulated in the ER, whereas other secretory proteins were transported at wild-type rates. In vitro budding experiments demonstrated that Erv26p was directly required for packaging of pro-ALP into COPII vesicles. Moreover, Erv26p was detected in a specific complex with pro-ALP when immunoprecipitated from detergent-solublized ER membranes. Based on these observations, we propose that Erv26p serves as a transmembrane adaptor to link specific secretory cargo to the COPII coat. Because ALP is a type II integral membrane protein in yeast, these findings imply that an additional class of secretory cargo relies on adaptor proteins for efficient export from the ER. INTRODUCTIONThe eukaryotic secretory pathway transports a remarkable variety of cargo proteins to their proper cellular location. Several lines of evidence indicate that targeting information encoded within a secretory protein is recognized by the intracellular transport machinery to direct localization. Cytosolic coat protein complexes play an important role in deciphering targeting information and act in the selection of secretory proteins into appropriate transport intermediates (Bonifacino and Glick, 2004). However, the sorting signals and mechanisms by which coat complexes accommodate such diversity in secretory cargo remain poorly understood.Protein transport from the endoplasmic reticulum (ER) relies on coat protein complex II (COPII), which selects fully folded secretory cargo into ER-derived transport intermediates. COPII coats consist of the small GTPase Sar1p, the Sec23/24 complex, and the Sec13/31 complex (Barlowe et al., 1994). Biochemical and structural studies have demonstrated that the Sec24p subunit of this coat complex contains multiple cargo recognition sites and binds specific sorting signals displayed on the cytosolic regions of secretory proteins (Miller et al., 2003;Mossessova et al., 2003). Diacidic sequences and other polypeptide sorting signals have been identified in cargo proteins that interact with amino acid residues within defined Sec24p cargo recognition sites. Current models envisage that the cargo recognition and binding by Sec24p is stabilized through assembly of prebudding complexes consisting of Sec23/24 and Sar1p-GTP bound to secretory cargo on the ER membrane surface. These prebudding complexes are then incorporated into an outer layer Sec13/31 scaffold structure that deforms the membrane and produces COPII-coated vesicles (Lee et al., 2004;Stagg et al., 2006).In addition to the COPII coat proteins, cargo-specific accessory factors are required to accommodate the variety of secretory cargo exported from the ER in CO...

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Section: Discussionmentioning

confidence: 60%

Erv26p Directs Pro-Alkaline Phosphatase into Endoplasmic Reticulum–derived Coat Protein Complex II Transport Vesicles

Bue

Bentivoglio

Barlowe

2006

MBoC

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“…ERGIC-53 is a hexameric type I membrane protein in complex with the luminal EF-hand protein MCFD2 (Zhang et al, 2003;Nyfeler et al, 2006). This cargo receptor complex cycles between ER and ERGIC (Klumperman et al, 1998;Nyfeler et al, 2006), and it facilitates ER-to-ERGIC transport of the lysosomal enzymes glycoproteins cathepsin C (Vollenweider et al, 1998;Nyfeler et al, 2005), cathepsin Z (Appenzeller et al, 1999), and the blood coagulation factors V and VIII (Nichols et al, 1998;Zhang et al, 2003). MCFD2 is dispensThis article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E07-10 -0989) on February 20, 2008. able for the transport of the lysosomal enzymes, but it required for the transport of factors V and VIII (Nyfeler et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

The Cargo Receptors Surf4, Endoplasmic Reticulum-Golgi Intermediate Compartment (ERGIC)-53, and p25 Are Required to Maintain the Architecture of ERGIC and Golgi

Mitrović

Ben-Tekaya

Koegler

et al. 2008

MBoC

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115

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Rapidly cycling proteins of the early secretory pathway can operate as cargo receptors. Known cargo receptors are abundant proteins, but it remains mysterious why their inactivation leads to rather limited secretion phenotypes. Studies of Surf4, the human orthologue of the yeast cargo receptor Erv29p, now reveal a novel function of cargo receptors. Surf4 was found to interact with endoplasmic reticulum-Golgi intermediate compartment (ERGIC)-53 and p24 proteins. Silencing Surf4 together with ERGIC-53 or silencing the p24 family member p25 induced an identical phenotype characterized by a reduced number of ERGIC clusters and fragmentation of the Golgi apparatus without effect on anterograde transport. Live imaging showed decreased stability of ERGIC clusters after knockdown of p25. Silencing of Surf4/ERGIC-53 or p25 resulted in partial redistribution of coat protein (COP) I but not Golgi matrix proteins to the cytosol and partial resistance of the cis-Golgi to brefeldin A. These findings imply that cargo receptors are essential for maintaining the architecture of ERGIC and Golgi by controlling COP I recruitment. INTRODUCTIONThe secretory pathway of higher eukaryotic cells is composed of the three membrane organelles endoplasmic reticulum (ER), ER-Golgi intermediate compartment (ERGIC), and Golgi (Bonifacino and Glick, 2004;Appenzeller-Herzog and Hauri, 2006). Maintenance of these organelles requires a balance of anterograde (secretory) and retrograde vesicular traffic. Anterograde traffic from ER to ERGIC is mediated by coat protein (COP) II vesicles that form at ER exit sites (Aridor et al., 1995;Zeuschner et al., 2006) and fuse with the ERGIC that consists of a few hundred tubulovesicular membrane clusters in vicinity of ER exit sites (AppenzellerHerzog and Hauri, 2006). Transport from ERGIC to Golgi is mediated by pleomorphic vesicles (Ben-Tekaya et al., 2005) that carry COP I (Presley et al., 1997;Scales et al., 1997), although the mechanism of their formation remains unknown. Retrograde traffic mediated by COP I vesicles can occur from ERGIC or Golgi and recycles membrane proteins that possess either dilysine signals, including ERGIC-53 and KDEL-receptor, or diphenylalanine signals, such as members of the 24 protein family. This rapid COP I-dependent recycling is distinct from the slow Golgi-to-ER recycling of Golgi resident proteins that is COP I independent and can be either constitutive or induced (Storrie, 2005).Major constituents of anterograde and retrograde transport vesicles are transmembrane cargo receptors that mediate protein sorting by linking soluble cargo on the luminal side and coat assembly on the cytoplasmic side. To date, only few cargo receptors have been studied in detail. The polytopic transmembrane protein Erv29p is known to cycle between ER and Golgi in yeast and to operate as a cargo receptor (Belden and Barlowe, 2001). Erv29p is required for efficient packaging of the glycosylated ␣-factor pheromone precursor into COP II vesicles departing from the ER. Maturation of carboxypeptidase Y...

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“…It is assumed that cargo receptors are responsible for such concentration of cargo into COP II vesicles. For some soluble glycoproteins, the cargo receptors have been identified as members of the emp24 family or as the lectin ERGIC53 (13,(30)(31)(32). By analogy, it could be assumed that MHC class I molecules require the interaction with cargo receptors for concentration and forward transport.…”

Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus Immediate Early Glycoprotein US3 Retains MHC Class I Molecules by Transient Association

Gruhler¹,

Peterson²,

Früh³

2000

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Human cytomegalovirus (HCMV) interferes with major histocompatibility complex (MHC) class I antigen presentation by a sequential multistep process to escape T cell surveillance. During the immediate early phase of infection, the glycoprotein US3 prevents intracellular transport of MHC class I molecules. Interestingly, US3 displays a significantly shorter half-life than US3-retained MHC class I molecules. Here we show that US3 associates only transiently with MHC class I molecules, exits the ER, and is inefficiently retrieved from the Golgi. US3 was degraded in a post-Golgi compartment, most likely lysosomes, because: i) Brefeldin A treatment prolonged the half-life of US3; and ii) US3 co-localized with the lysosomal marker protein LAMP in chloroquinetreated cells. In contrast, MHC class I molecules remained stable in the ER. Upon inhibition of protein synthesis MHC class I molecules were released suggesting that a continuous supply of newly synthesized US3 molecules is required for inhibition of transport. Thus, US3 does not seem to retain MHC class I molecules by a retrieval mechanism. Instead, our observations are consistent with US3 preventing MHC class I trafficking by blocking forward transport.

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Mutations in the ER–Golgi Intermediate Compartment Protein ERGIC-53 Cause Combined Deficiency of Coagulation Factors V and VIII

Cited by 427 publications

References 56 publications

Erv26p Directs Pro-Alkaline Phosphatase into Endoplasmic Reticulum–derived Coat Protein Complex II Transport Vesicles

Erv26p Directs Pro-Alkaline Phosphatase into Endoplasmic Reticulum–derived Coat Protein Complex II Transport Vesicles

The Cargo Receptors Surf4, Endoplasmic Reticulum-Golgi Intermediate Compartment (ERGIC)-53, and p25 Are Required to Maintain the Architecture of ERGIC and Golgi

Human Cytomegalovirus Immediate Early Glycoprotein US3 Retains MHC Class I Molecules by Transient Association

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