ER-to-Golgi transport receptor in regulating coagulation factors V and VIII Coagulation factor V (FV) and factor VIII (FVIII) are both secreted glycoproteins that share pivotal roles in both hemostasis and thrombosis. Although many secreted proteins (referred to as cargo) are believed to require transport receptors for efficient ER-to-Golgi transport, only a limited number of such receptors have been described, mostly in yeast. Evidence for the existence of mammalian cargo receptors came unexpectedly from studies of the human genetic disorder combined deficiency of FV and FVIII, which identified mutations in LMAN1 and MCFD2 as the cause of the disorder. Combined deficiency of FV and FVIII is a rare bleeding disorder characterized by the reduction of both FV and FVIII to 5-30% of normal. LMAN1 and MCFD2 form a Ca2+-dependent protein complex in the ER-Golgi intermediate compartment that interacts with FV and FVIII, suggesting that the LMAN1-MCFD2 complex is a cargo receptor required for efficient transport of FV and FVIII from the ER to the Golgi. The requirement of both a transmembrane component (LMAN1) and a soluble cofactor (MCFD2) suggests a more sophisticated mechanism for cargo trafficking in higher eukaryotes, and could represent a paradigm for the organization of other mammalian cargo receptors. We hypothesize that dual sorting signals on FV and FVIII are separately recognized by LMAN1 and MCFD2. The proposed studies will identify these sorting signals that regulate cargo binding and release, investigate the ER-to-Golgi transport deficiency as a novel mechanism of hemophilia A and use mouse models to investigate LMAN1-MCFD2 mediated secretion of FV and FVIII in vivo. Results will not only answer fundamental questions regarding the mechanism of LMAN1-MCFD2 receptor-mediated secretion of FV and FVIII, but will also provide fundamental new insight into general mechanism of mammalian ER-to-Golgi protein transport. Genetic deficiency of FVIII results in hemophilia A, which affects ~1 in 5000 males. On the other hand, a gain-of-function mutation in FV (FV Leiden) and increased FVIII activity are major risk factors for venous thrombosis, which affects ~1:1,000 individuals in the US per year. The findings will have practical importance for improving FVIII expression and may expedite the eventual goal of somatic cell gene therapy for hemophilia A, as well as new approaches to limiting FV and FVIII production in prothrombotic states.

Public Health Relevance

The project will study a protein transport receptor that is required for the secretion of blood clotting factor V and factor VIII. The goal is to understand how this transport receptor works and hopefully use the knowledge to develop better treatment for bleeding and thrombotic diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Link, Rebecca P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
Zip Code
Khoriaty, Rami; Everett, Lesley; Chase, Jennifer et al. (2016) Pancreatic SEC23B deficiency is sufficient to explain the perinatal lethality of germline SEC23B deficiency in mice. Sci Rep 6:27802
Yehia, Lamis; Niazi, Farshad; Ni, Ying et al. (2015) Germline Heterozygous Variants in SEC23B Are Associated with Cowden Syndrome and Enriched in Apparently Sporadic Thyroid Cancer. Am J Hum Genet 97:661-76
Zhu, Min; Tao, Jiayi; Vasievich, Matthew P et al. (2015) Neural tube opening and abnormal extraembryonic membrane development in SEC23A deficient mice. Sci Rep 5:15471
Khoriaty, Rami; Vasievich, Matthew P; Jones, Morgan et al. (2014) Absence of a red blood cell phenotype in mice with hematopoietic deficiency of SEC23B. Mol Cell Biol 34:3721-34
Hao, Hong; Gregorski, Janina; Qian, Haohua et al. (2014) In vivo function of the ER-Golgi transport protein LMAN1 in photoreceptor homeostasis. Adv Exp Med Biol 801:395-9
Baines, Andrea C; Adams, Elizabeth J; Zhang, Bin et al. (2013) Disruption of the Sec24d gene results in early embryonic lethality in the mouse. PLoS One 8:e61114
Zheng, Chunlei; Page, Richard C; Das, Vaijayanti et al. (2013) Structural characterization of carbohydrate binding by LMAN1 protein provides new insight into the endoplasmic reticulum export of factors V (FV) and VIII (FVIII). J Biol Chem 288:20499-509
Klaus, Joseph P; Eisenhauer, Philip; Russo, Joanne et al. (2013) The intracellular cargo receptor ERGIC-53 is required for the production of infectious arenavirus, coronavirus, and filovirus particles. Cell Host Microbe 14:522-34
Zheng, Chunlei; Zhang, Bin (2013) Combined deficiency of coagulation factors V and VIII: an update. Semin Thromb Hemost 39:613-20
Patel, A J; Liu, H-H; Lager, R A et al. (2013) Successful percutaneous coronary intervention in a patient with combined deficiency of FV and FVIII due to novel compound heterozygous mutations in LMAN1. Haemophilia 19:607-10

Showing the most recent 10 out of 17 publications