FVIII is secreted

Stable Identifier
R-HSA-9661625
Type
Reaction [uncertain]
Species
Homo sapiens
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Coagulation factor VIII (FVIII) is a large glycoprotein of 2351 aminoacids with a discrete domain structure: A1-A2-B-A3-C1-C2 (Wood WI et al. 1984; Vehar GA et al. 1984; Toole JJ et al. 1984). FVIII is synthesized by various tissues, including liver, kidney, and spleen, as an inactive single-chain protein of approximately 293 kDa (Wion KL et al. 1985; Levinson B et al. 1992). Primary human liver sinusoidal endothelial cells (LSECs), blood outgrowth endothelial cells (BOEC), glomerular microvascular endothelial cells (GMVECs) and umbilical vein endothelial cells (HUVECs) were found to produce the FVIII protein, store it in Weibel-Palade bodies (WPB), and secrete in response to EC stimulation (van den Biggelaar M et al. 2009; Shahani T et al. 2014; Turner NA & Moake JL 2015). These findings are in agreement with the reports on the FVIII synthesis in human cultured ECs and in mice suggesting that ECs are the predominant source of plasma FVIII (Jacquemin M et al. 2006; Shahani T et al. 2010; Fahs SA et al. 2014). Evidence on the post-translational processing and secretion of FVIII has been generated from expression of the FVIII complementary DNA (cDNA) in transfected mammalian cells, such as Chinese hamster ovary (CHO), African green monkey kidney (COS-1), HeLa and the human hepatic SK-HEP1cell lines (Pipe SW et al. 1998; Herlitschka SE et al. 1998). Upon synthesis, FVIII is translocated into the lumen of the endoplasmic reticulum (ER), where it undergoes extensive processing including cleavage of a signal peptide and N-linked glycosylation at asparagine residues (Kaufman RJ et al. 1988, 1997; Kaufman RJ 1998). In the ER lumen of mammalian cells FVIII interacts with the protein chaperones calnexin (CNX), calreticulin (CRT), and immunoglobulin-binding protein (BiP or GRP78) that facilitate proper folding of proteins prior to trafficking to the Golgi compartment (Marquette KA et al. 1995; Swaroop M et al. 1997; Pipe SW et al. 1998; Kaufman RJ et al. 1997; Kaufman RJ 1998). Trafficking from the ER to the Golgi compartment is facilitated by LMAN1 and multiple combined factor deficiency 2 (MCFD2) cargo receptor complex (Zhang B et al. 2005; Zheng, C et al. 2010, 2013). Within the Golgi apparatus, FVIII is subject to further processing, including modification of the N-linked oligosaccharides to complex-type structures, O-linked glycosylation, and sulfation of specific Tyr-residues (Michnick DA et al. 1994; Kaufman RJ 1998). In addition, factor VIII is among the many proteins that undergoes intracellular proteolysis. Upon secretion from the cell, FVIII is cleaved at two sites in the B-domain to form a heterodimer consisting of the heavy chain containing the A1-A2-B domains in a metal ion-dependent complex with the light chain consisting of the A3-C1-C2 domains (Kaufman RJ et al. 1997; Kaufman RJ 1998). In the plasma, FVIII is stabilized through interaction with von Willebrand factor (Weiss HJ et al. 1977; Kaufman RJ et al. 1988; Chiu PL et al. 2015). Upon damage to blood vessel walls, thrombin cleaves FVIII and releases the B-domain to form an active FVIII heterotrimer (A1:A2:A3-C1-C2) that binds activated coagulation factor IX on the surface of platelet phospholipid to form the active factor Xase complex (Ahmad SS et al. 2003; Panteleev MA et al. 2006). This complex efficiently cleaves factor X to its active form, which activates prothrombin and leads to the formation of a stable fibrin clot. After conversion into its active conformation, and participation in the factor X activating complex, activated factor VIII rapidly looses its activity (Kaufman RJ et al. 1988; Lenting PJ et al. 1998). This process is governed by both enzymatic degradation and subunit dissociation. At the cellular level the FVIII expression is limited. Inefficient secretion of FVIII is caused by repression at the level of transcription (Lynch CM et al. 1993; Hoeben RC et al. 1995). In addition, a significant portion of the primary translation product is misfolded and ultimately degraded and FVIII is retained within ER through interaction with various ER chaperones including BiP (Marquette KA et al. 1995; Tagliavacca L et al. 2000). Mutations in the F8 gene often result in diminished or inactive plasma factor VIII protein and are the molecular genetic cause of the monogenic, X-linked, bleeding disorder hemophilia A (Al-Allaf FA et al. 2017; Castaman G & Matino D 2019).

Literature References
PubMed ID Title Journal Year
9834200 The life cycle of coagulation factor VIII in view of its structure and function

Lenting, PJ, van Mourik, JA, Mertens, K

Blood 1998
3129422 Synthesis, processing, and secretion of recombinant human factor VIII expressed in mammalian cells

Kaufman, RJ, Wasley, LC, Dorner, AJ

J. Biol. Chem. 1988
7727775 Expression of the blood-clotting factor-VIII cDNA is repressed by a transcriptional silencer located in its coding region

Hoeben, RC, Fallaux, FJ, Cramer, SJ, van den Wollenberg, DJ, van Ormondt, H, Briƫt, E, van der Eb, AJ

Blood 1995
26473492 Factor VIII Is Synthesized in Human Endothelial Cells, Packaged in Weibel-Palade Bodies and Secreted Bound to ULVWF Strings

Turner, NA, Moake, JL

PLoS ONE 2015
9607108 Biosynthesis, assembly and secretion of coagulation factor VIII

Kaufman, RJ, Pipe, SW, Tagliavacca, L, Swaroop, M, Moussalli, M

Blood Coagul. Fibrinolysis 1997
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