The COPII pathway and hematologic disease

Department of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA.
Blood (Impact Factor: 10.45). 05/2012; 120(1):31-8. DOI: 10.1182/blood-2012-01-292086
Source: PubMed


Multiple diseases, hematologic and nonhematologic, result from defects in the early secretory pathway. Congenital dyserythropoietic anemia type II (CDAII) and combined deficiency of coagulation factors V and VIII (F5F8D) are the 2 known hematologic diseases that result from defects in the endoplasmic reticulum (ER)-to-Golgi transport system. CDAII is caused by mutations in the SEC23B gene, which encodes a core component of the coat protein complex II (COPII). F5F8D results from mutations in either LMAN1 (lectin mannose-binding protein 1) or MCFD2 (multiple coagulation factor deficiency protein 2), which encode the ER cargo receptor complex LMAN1-MCFD2. These diseases and their molecular pathogenesis are the focus of this review.

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    • "In this study GCDH, DLST, ETFB and ETFA were C-terminally either tagged with YFP1 (amino acids 1–158) or YFP2 (amino acids from 159 to 239) (Fig. 5A and 6A). As negative controls, we included the multiple coagulation factor deficiency protein 2 (MCFD2), localized in the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) [23], and the mitochondrial matrix enzyme 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) [24]. Individual expression of different YFP1- and YFP2-fusion proteins in BHK cells was confirmed by western blotting. "
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    ABSTRACT: Glutaric aciduria type 1 (GA1) is an inherited neurometabolic disorder caused by mutations in the GCDH gene encoding glutaryl-CoA dehydrogenase (GCDH), which forms homo- and heteromeric complexes in the mitochondrial matrix. GA1 patients are prone to the development of encephalopathic crises which lead to an irreversible disabling dystonic movement disorder. The clinical and biochemical manifestations of GA1 vary considerably and lack correlations to the genotype. Using an affinity chromatography approach we report here for the first time on the identification of mitochondrial proteins interacting directly with GCDH. Among others, dihydrolipoamide S-succinyltransferase (DLST) involved in the formation of glutaryl-CoA, and the β-subunit of the electron transfer flavoprotein (ETFB) serving as electron acceptor, were identified as GCDH binding partners. We have adapted the yellow fluorescent protein-based fragment complementation assay and visualized the oligomerization of GCDH as well as its direct interaction with DLST and ETFB in mitochondria of living cells. These data suggest that GCDH is a constituent of multimeric mitochondrial dehydrogenase complexes, and the characterization of their interrelated functions may provide new insights into the regulation of lysine oxidation and the pathophysiology of GA1.
    PLoS ONE 02/2014; 9(2):e87715. DOI:10.1371/journal.pone.0087715 · 3.23 Impact Factor
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    • "using a proteomics-based approach to identify candidate antiviral targets. In conclusion, ERGIC-53 represents a potential antiviral target because of its clearly demonstrated importance for the replication of pathogenic arenaviruses, coronaviruses, and filoviruses and the fact that loss of this protein or its function is well tolerated in humans (Khoriaty et al., 2012 "
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    ABSTRACT: Arenaviruses and hantaviruses cause severe human disease. Little is known regarding host proteins required for their propagation. We identified human proteins that interact with the glycoproteins (GPs) of a prototypic arenavirus and hantavirus and show that the lectin endoplasmic reticulum (ER)-Golgi intermediate compartment 53 kDa protein (ERGIC-53), a cargo receptor required for glycoprotein trafficking within the early exocytic pathway, associates with arenavirus, hantavirus, coronavirus, orthomyxovirus, and filovirus GPs. ERGIC-53 binds to arenavirus GPs through a lectin-independent mechanism, traffics to arenavirus budding sites, and is incorporated into virions. ERGIC-53 is required for arenavirus, coronavirus, and filovirus propagation; in its absence, GP-containing virus particles form but are noninfectious, due in part to their inability to attach to host cells. Thus, we have identified a class of pathogen-derived ERGIC-53 ligands, a lectin-independent basis for their association with ERGIC-53, and a role for ERGIC-53 in the propagation of several highly pathogenic RNA virus families.
    Cell host & microbe 11/2013; 14(5):522-34. DOI:10.1016/j.chom.2013.10.010 · 12.33 Impact Factor
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    • "Rather, these observations suggest that the specific functions of the vertebrate SEC24s, mediated either through unique cargo selectivity or tissue-specific expression programs, may have shifted over evolutionary time. Consistent with this notion, the phenotypes of SEC23B deficiency differ markedly between humans, mice and zebrafish [21], [22], [23], [36]. "
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    ABSTRACT: Transport of newly synthesized proteins from the endoplasmic reticulum (ER) to the Golgi is mediated by the coat protein complex COPII. The inner coat of COPII is assembled from heterodimers of SEC23 and SEC24. Though mice with mutations in one of the four Sec24 paralogs, Sec24b, exhibit a neural tube closure defect, deficiency in humans or mice has not yet been described for any of the other Sec24 paralogs. We now report characterization of mice with targeted disruption of Sec24d. Early embryonic lethality is observed in mice completely deficient in SEC24D, while a hypomorphic Sec24d allele permits survival to mid-embryogenesis. Mice haploinsufficient for Sec24d exhibit no phenotypic abnormality. A BAC transgene containing Sec24d rescues the embryonic lethality observed in Sec24d-null mice. These results demonstrate an absolute requirement for SEC24D expression in early mammalian development that is not compensated by the other three Sec24 paralogs. The early embryonic lethality resulting from loss of SEC24D in mice contrasts with the previously reported mild skeletal phenotype of SEC24D deficiency in zebrafish and restricted neural tube phenotype of SEC24B deficiency in mice. Taken together, these observations suggest that the multiple Sec24 paralogs have developed distinct functions over the course of vertebrate evolution.
    PLoS ONE 04/2013; 8(4):e61114. DOI:10.1371/journal.pone.0061114 · 3.23 Impact Factor
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