A review of the expression, assembly, secretion and intracellular degradation of fibrinogen

Abstract

The expression, assembly and secretion of fibrinogen are reviewed. Fibrinogen, the product of three exquisitely controlled genes, has a high basal level of expression and its production is further greatly increased in response to infection and/or tissue damage. In hepatocytes, the principal source of plasma fibrinogen, constitutive expression of the Aα and Bβ genes is mostly dependent on HNF-1 while the γ gene depends on at least three ubiquitous transcription factors. As a member of the acute phase proteins, fibrinogen expression is up-regulated by interleukin-6 (IL-6) and the glucocorticoids causing a coordinated expression of all three genes. IL-6 up-regulation of the fibrinogen genes involves activation of the STAT-3 and C/EBP transcription factors. Fibrinogen chain assembly occurs in the endoplasmic reticulum (ER) in a step-wise manner in which single chains form two-chain complexes (Aα-γ and Bβ-γ) which subsequently acquire a third chain to form a half-molecule. In a final step the two half-molecules are joined to form fibrinogen. Chain assembly is facilitated by chaperones and distinct structural domains of fibrinogen are necessary for proper assembly. Removal of the C-terminal half of the coiled coil region of the chains prevents chain assembly and disruption of the disulfide rings that flank the proximal N-terminal portion of the coiled-coil, or deletion of the N-terminal half of the coiled-coil, prevents half-molecules from forming dimers. Intracellular proteolysis plays a role in the regulation of fibrinogen chain assembly. Hepatocytes contain surplus Aα and γ chains and the ubiquitin-proteasome pathway is involved in degrading unassembled Bβ and γ chains. Aα-γ complexes are degraded by lysosomes.