Novel mechanism underlying fibrinogen biogenesis in the endoplasmic reticulum

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A large number of diseases are now recognized as ‘conformational diseases’, caused by protein misfolding and subsequent aggregation. One example is hepatic fibrinogen storage disease (HFSD), where the underlying cause is the endoplasmic reticulum (ER) retention and aggregation of fibrinogen mutants, leading to liver damage, hypofibrinogenemia, and excessive bleeding. However, the molecular events underlying the biogenesis and quality control of, both wildtype and mutant fibrinogen, in the ER remain unknown. In the preliminary data of this application, we serendipitously found that the biogenesis of fibrinogen is regulated by the Sel1L-Hrd1 protein complex of the principal ER quality-control machinery, ER-associated degradation (ERAD). Sel1L-Hrd1 ERAD represents the most evolutionarily conserved branch of ERAD and targets misfolded ER proteins for cytosolic proteasomal degradation. Hepatocyte-specific Sel1L-deficient mice exhibit fibrinogen-containing inclusions in the ER of hepatocytes, hepatic damage and hypofibrinogenemia, resembling human patients with HFSD. Indeed, both wildtype and disease-causing mutants of fibrinogens are degraded by Sel1L-Hrd1 ERAD. These data point to a critical role of hepatocyte Sel1L-Hrd1 ERAD in fibrinogen biogenesis and live homeostasis. Hence, the overarching hypothesis of this application is that Sel1L-Hrd1 ERAD is a critical regulatory mechanism for fibrinogen biogenesis, coagulation and liver homeostasis by targeting misfolded, either wildtype or mutant, fibrinogen proteins for proteasomal degradation. This action of ERAD towards fibrinogen prevents the formation of toxic fibrinogen inclusions and aggregates in the liver. We will accomplish two Aims: (1) Demonstrate the significance and molecular mechanism of hepatic Sel1L-Hrd1 ERAD in coagulation and fibrinogen biogenesis; and (2) Delineate the pathological importance of Sel1L-Hrd1 ERAD in HFSD. Completion of these studies will not only delineate the significance and molecular mechanism underlying the ERAD function in early biogenesis of fibrinogen, but also have broader impact on the mechanism and therapeutical strategy for other conformational diseases associated with protein misfolding.