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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    • "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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    • "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.
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