Mcfd2, or multiple coagulation factor deficiency 2, is an EF-hand domain-containing protein. It forms a calcium-dependent heteromeric complex with LMAN1 (ERGIC-53), a mannose-specific lectin. This LMAN1-Mcfd2 complex functions as a cargo receptor in the endoplasmic reticulum (ER)-to-Golgi transport pathway, which is crucial for the efficient secretion of various glycoproteins, such as coagulation factors V (FV) and VIII (FVIII), and α1-antitrypsin (AAT) [1,3,4,5,6]. Genetic models, like knockout (KO) mice, have been instrumental in studying its function.

In Mcfd2-deficient mice, plasma levels of FV and FVIII are reduced, with levels even lower than those in LMAN1-deficient mice [4]. This indicates Mcfd2's importance in the ER-to-Golgi transport of these coagulation factors. Additionally, male Mcfd2-deficient mice also show decreased plasma levels of AAT, along with its accumulation in hepatocyte ER, suggesting Mcfd2's role in the efficient ER exit of AAT [4]. RNAi targeting Mcfd2 in mice leads to effective inhibition of its expression, prolongs APTT, and decreases FVIII activity, showing potential as an anticoagulant approach [2].

In conclusion, Mcfd2 is essential for the ER-to-Golgi transport of key glycoproteins, including coagulation factors and AAT. Studies using Mcfd2-deficient mouse models have revealed its role in bleeding disorders related to combined FV and FVIII deficiency and potentially in diseases associated with AAT deficiency. These findings contribute to understanding the molecular mechanisms of these diseases and developing new treatment strategies.

References:

1. Zhang, Yuan, Zhu, Min, Zheng, Chunlei, Emmer, Brian T, Zhang, Bin. . LMAN1-MCFD2 complex is a cargo receptor for the ER-Golgi transport of α1-antitrypsin. In The Biochemical journal, 479, 839-855. doi:10.1042/BCJ20220055. https://pubmed.ncbi.nlm.nih.gov/35322856/

2. Ma, Siqian, Liu, Boyan, Du, Hong, Ji, Shundong, Jiang, Miao. 2024. RNAi targeting LMAN1-MCFD2 complex promotes anticoagulation in mice. In Journal of thrombosis and thrombolysis, 57, 1349-1362. doi:10.1007/s11239-024-03034-6. https://pubmed.ncbi.nlm.nih.gov/39222205/

3. Zhang, Yuan, Liu, Zhigang, Zhang, Bin. . Separate roles of LMAN1 and MCFD2 in ER-to-Golgi trafficking of FV and FVIII. In Blood advances, 7, 1286-1296. doi:10.1182/bloodadvances.2022008788. https://pubmed.ncbi.nlm.nih.gov/36490287/

4. Zhu, Min, Zheng, Chunlei, Wei, Wei, Ginsburg, David, Zhang, Bin. . Analysis of MCFD2- and LMAN1-deficient mice demonstrates distinct functions in vivo. In Blood advances, 2, 1014-1021. doi:10.1182/bloodadvances.2018018317. https://pubmed.ncbi.nlm.nih.gov/29735583/

5. Zhang, Bin. 2009. Recent developments in the understanding of the combined deficiency of FV and FVIII. In British journal of haematology, 145, 15-23. doi:10.1111/j.1365-2141.2008.07559.x. https://pubmed.ncbi.nlm.nih.gov/19183188/

6. Zheng, Chunlei, Zhang, Bin. 2013. Combined deficiency of coagulation factors V and VIII: an update. In Seminars in thrombosis and hemostasis, 39, 613-20. doi:10.1055/s-0033-1349223. https://pubmed.ncbi.nlm.nih.gov/23852824/