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  • Title: Differential degradation of the three fibrinogen chains by proteasomes: involvement of Sec61p and cytosolic Hsp70.
    Author: Xia H, Redman CM.
    Journal: Arch Biochem Biophys; 2001 Jun 01; 390(1):137-45. PubMed ID: 11368525.
    Abstract:
    HepG2 cells, which synthesize and secrete fibrinogen, accumulate surplus Aalpha and gamma chains. The nonsecreted fibrinogen chains are degraded both by proteasomes and lysosomes, with unassembled chains primarily degraded by proteasomes and an Aalpha-gamma complex by lysosomes. To further determine the mechanisms by which unassembled fibrinogen chains are degraded, and to explain the pools of Aalpha and gamma chains that occur in HepG2 cells, the association of fibrinogen chains with Sec61beta, a component of the translocon, and with a cytosol chaperone, Hsp70, was studied in both HepG2 cells and COS cells expressing single fibrinogen chains. Retrotranslocation from the lumen of the endoplasmic reticulum was shown by treatment with MG132, a proteasome inhibitor. MG132 caused glycosylated Bbeta to accumulate on Sec61beta in COS cells expressing Bbeta and acted similarly with all three fibrinogen chains in HepG2 cells. In HepG2 cells, Bbeta was associated with Sec61beta ahead of Aalpha and gamma chains, suggesting that pools of Aalpha and gamma chains may be caused by unequal rates of retrotranslocation. In COS cells, retrotranslocation into the cytoplasm was demonstrated by the ATP-sensitive association of ubiquitinylated Aalpha, Bbeta, and gamma chains bound to Hsp70. More Aalpha and gamma than Bbeta accumulated on Hsp70 of HepG2 cells, consistent with more rapid degradation of Bbeta. Overexpression of Hsp70 in HepG2 cells resulted in decreased secretion, but not synthesis, of fibrinogen. Decreased secretion may be due to enhanced degradation of unassembled fibrinogen chains, indicating that proteolysis by proteasomes might regulate both the intracellular pools of fibrinogen chains and fibrinogen secretion.
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