Molecular basis of LMAN1 in coordinating LMAN1-MCFD2 cargo receptor formation and ER-to-Golgi transport of FV/FVIII

Zheng, Chunlei; Liu, Hui Hui; Yuan, Shuguang; Zhou, Jiahai; Zhang, Bin

doi:10.1182/blood-2010-04-278325

Cited by 59 publications

(78 citation statements)

References 41 publications

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“…Cryosections (6 μm) were stained with H&E for histological analysis. Immunofluorescence staining was performed on PFA-fixed cryosections as described previously (44). TUNEL staining was performed according to the manufacturer's instructions (Roche Diagnostics).…”

Section: Methodsmentioning

confidence: 99%

“…COS1 cells were cultured in DMEM supplemented with 10% (vol/vol) FBS and transfected with plasmids expressing GFP-SEC23A or GFP-SEC23B fusion proteins. Cells were lysed with Nonidet P-40 buffer (44), and the total protein levels were quantified by using the Bradford assay (Bio-Rad). To compare the amounts of SEC23A and SEC23B fusion proteins, we first performed standard Western blot analyses on serial dilutions of cell lysates by using antibodies against GFP and β-actin.…”

Section: Methodsmentioning

confidence: 99%

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SEC23B is required for the maintenance of murine professional secretory tissues

Tao

Zhu

Wang

et al. 2012

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

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105

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In eukaryotic cells, newly synthesized secretory proteins require COPII (coat protein complex II) to exit the endoplasmic reticulum (ER). COPII contains five core components: SAR1, SEC23, SEC24, SEC13, and SEC31. SEC23 is a GTPase-activating protein that activates the SAR1 GTPase and also plays a role in cargo recognition. Missense mutations in the human COPII paralogues SEC23A and SEC23B result in craniolenticulosutural dysplasia and congenital dyserythropoietic anemia type II, respectively. We now report that mice completely deficient for SEC23B are born with no apparent anemia phenotype, but die shortly after birth, with degeneration of professional secretory tissues. In SEC23B-deficient embryonic pancreas, defects occur in exocrine and endocrine tissues shortly after differentiation. Pancreatic acini are completely devoid of zymogen granules, and the ER is severely distended. Similar ultrastructural alterations are also observed in salivary glands, but not in liver. Accumulation of proteins in the ER lumen activates the proapoptotic pathway of the unfolded protein response, suggesting a central role for apoptosis in the degeneration of these tissues in SEC23B-deficient embryos. Although maintenance of the secretory pathway should be required by all cells, our findings reveal a surprising tissue-specific dependence on SEC23B for the ER exit of highly abundant cargo, with high levels of SEC23B expression observed in professional secretory tissues. The disparate phenotypes in mouse and human could result from residual SEC23B function associated with the hypomorphic mutations observed in humans, or alternatively, might be explained by a species-specific shift in function between the closely related SEC23 paralogues. mammalian embryo abnormalities | vesicular transport protein | genetics | secretory granules | pancreatitis I n eukaryotic cells, secreted proteins and proteins that are targeted to the plasma membrane and internal organelles are synthesized in the endoplasmic reticulum (ER) and sorted through the secretory pathway. This process has been extensively studied, particularly in budding yeast (1). Proteins destined to traffic from the ER to the Golgi are packaged into COPII (coat protein complex II)-coated vesicles (2-4). COPII is composed of at least five proteins, a small GTPase SAR1 and two cytosolic protein complexes, SEC23-SEC24 and SEC13-SEC31 (5). The GTP-bound form of SAR1 binds to the ER membrane and recruits the SEC23-SEC24 heterodimer to form the "prebudding complex," which in turn recruits the outer coat composed of SEC13-SEC31 heterotetramers to complete the COPII coat structure (6).The COPII complex captures cargo into vesicles and mediates vesicle budding from the ER. Cargo recognition appears to be mediated primarily by the SEC24 subunit, which recognizes divergent export signals located in the cytosolic domain of cargo proteins (7,8). SEC23 and SAR1 also play a role in the recognition of at least a subset of cargos (9, 10). SEC23 is a GTPaseactivating protein (GAP) that activates the SAR1...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

SEC23B is required for the maintenance of murine professional secretory tissues

Tao

Zhu

Wang

et al. 2012

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

Self Cite

105

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“…67 This is also important for MCFD2 binding. 68 MCFD2 lacks a KDEL ER retrieval signal, and therefore relies on its interaction with LMAN1 for proper trafficking. In the absence of LMAN1, MCFD2 is not recycled back to the ER and is instead secreted from the cell.…”

Section: Pathogenesis Of F5f8dmentioning

confidence: 99%

The COPII pathway and hematologic disease

Khoriaty

Vasievich

Ginsburg

2012

Blood

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IntroductionMultiple human diseases resulting from defects in the endoplasmic reticulum (ER)-to-Golgi transport have been reported over the past 14 years (Table 1). Anderson disease or chylomicron retention disorder (CMRD), 1 a disease characterized by malabsorption of lipids from the diet and accumulation of chylomicrons in the enterocytes, results from mutations in SAR1B, a component of coat protein complex II (COPII)-coated vesicles that bud from the surface of the ER and transport cargo proteins to the Golgi apparatus. Patients with CMRD exhibit failure to thrive in infancy, absence of circulating chylomicrons, low levels of plasma cholesterol, and deficiency of fat-soluble vitamins. Mutations in SEC23A, another component of the COPII coat, result in cranio-lenticulosutural-dysplasia (CLSD), 2 an autosomal recessive syndrome characterized by sutural cataracts, late closure of the cranial fontanelles, skeletal abnormalities, and dysmorphic facial features. Only 2 CLSD pedigrees have been reported, each with a different missense mutation. 2,3 Defects in the ER export machinery have been reported to cause 2 hematologic diseases, combined deficiency of coagulation factors V (FV) and VIII (FVIII) (F5F8D) and congenital dyserythropoietic anemia type II (CDAII). F5F8D is characterized by a decrease in FV and FVIII levels to ϳ 10% of normal with generally mild bleeding manifestations. This disorder results from mutations in either LMAN1 4 (lectin mannose-binding protein 1) or MCFD2 5 (multiple coagulation factor deficiency protein 2), 2 genes that encode the components of a specific ER cargo receptor for FV and FVIII. CDAII results from mutation in SEC23B, a paralog of SEC23A in mammals. CDAII is characterized by mild to moderate anemia, bi-or multinucleated erythroblasts, aberrant glycosylation of erythrocyte band 3, and red blood cell (RBC) lysis in some (but not all) acidified normal sera.Although no human diseases resulting from defects in other components of the early secretory pathway have been reported to date, animal models of defects in Sec24B, Sec24C, and Sec24D, have been described [6][7][8] (Table 1), again reflecting a range of manifestations, from no apparent phenotype (zebrafish Sec24C), 8 to a unique neural tube developmental defect (murine Sec24B) 7,12 to characteristic skeletal malformations (zebrafish Sec24D). 8 A general overview of the Mendelian disorders resulting from defects in the membrane trafficking machinery was recently published. 13 In this review, we focus on the 2 hematologic diseases F5F8D indicates combined deficiency of coagulation factors V and VIII; CMRD, chylomicron retention disorder; CLSD, cranio-lenticulo-sutural-dysplasia; CDAII, congenital dyserythropoietic anemia type II; and NR, none reported.*Morphant zebrafish models (where the zebrafish have been treated with a morpholino antisense oligonucleotide to "knockdown" the expression of the gene of interest). †Mutant zebrafish models. 31BLOOD, 5 JULY 2012 ⅐ VOLUME 120, NUMBER 1For personal use only. on April 28, 2019. by gue...

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“…To date, most cargo receptors are identified in yeast [72]. However, the LMAN1-MCFD2 protein complex is the only well-characterized cargo receptor in mammalian cells [70]. The majority of LMAN1 is localized to the ERGIC at steady state, it also cycles between the ER and ERGIC in live cells.…”

Section: Hematological Disordersmentioning

confidence: 99%

“…Both proteins form a stable Ca21-dependent complex with 1:1 stoichiometry that specifically aids in the transport of glycosylated FV and FVIII from the ER to the Golgi compartment. The intracellular localization of this complex at the ERGIC suggests a specific cargo receptor function for FV and FVIII in the early secretory pathway [69,70]. Cargo receptors are transmembrane proteins, required for the efficient ER to Golgi transport of many soluble secretory proteins.…”

Section: Hematological Disordersmentioning

confidence: 99%

Inherited hematological disorders due to defects in coat protein (COP)II complex

2012

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Many diseases attributed to trafficking defects are primary disorders of protein folding and assembly. However, an increasing number of disease states are directly attributable to defects in trafficking machinery. In this context, the cytoplasmic coat protein (COP)II complex plays a pivotal role: it mediates the anterograde transport of correctly folded secretory cargo from the endoplasmic reticulum towards the Golgi apparatus. This review attempts to describe the involvement of COPII complex alteration in the pathogenesis of human genetic disorders; particularly, we will focus on two disorders, the Congenital Dyserythropoietic Anemia type II and the Combined Deficiency of Factor V and VIII. Am. J. Hematol., 88:135–140, 2013. © 2012 Wiley Periodicals, Inc.

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Molecular basis of LMAN1 in coordinating LMAN1-MCFD2 cargo receptor formation and ER-to-Golgi transport of FV/FVIII

Cited by 59 publications

References 41 publications

SEC23B is required for the maintenance of murine professional secretory tissues

SEC23B is required for the maintenance of murine professional secretory tissues

The COPII pathway and hematologic disease

Inherited hematological disorders due to defects in coat protein (COP)II complex

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