The degradation of nascent fibrinogen chains is mediated by the ubiquitin proteasome pathway.
Recent studies have shown that ubiquitin-dependent proteolysis by proteasomes plays an essential role in the degradation of ER-retained proteins. We investigated the degradation of individual fibrinogen chains in transfected COS cells which express but do not secrete single chains. In transfected COS cells, the degradation of fibrinogen Bbeta and gamma chain was markedly inhibited by the proteasome inhibitors lactacystin and MG132. These specific proteasome inhibitors also partially affected the degradation of Aalpha chain. In HepG2 cells, which synthesize and secrete fibrinogen, the degradation of intracellular free gamma chain was also inhibited by MG132. We also detected high molecular weight polyubiquitinated forms of fibrinogen chains in transfected COS cells and in HepG2 cells by sequential immunoprecipitation. These results implicate proteasomes in the degradation of fibrinogen chains. In COS cells, gamma chains have a longer half-life than Bbeta chains and Aalpha chains, suggesting that the presence of surplus gamma chains in fibrinogen-producing cells is due to the unequal degradation rate of fibrinogen chains. These results indicate that the ubiquitin-proteasome pathway may be a major system for the degradation of unassembled fibrinogen chains.
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Lindsley F. Kimball Research Institute, The New York Blood Center, New York, New York, 10021, USA.
Redman
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D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D019556:COS Cells / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D005340:Fibrinogen / Q000378:metabolism*; D007163:Immunosorbent Techniques; D007976:Leupeptins / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D014162:Transfection; D014452:Ubiquitins / Q000378:metabolism*
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D009097:Multienzyme Complexes; D014452:Ubiquitins; C067713:lactacystin; D005340:Fibrinogen; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000111:Acetylcysteine