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(American Journal of Pathology. 2006;168:1299-1308.)
© 2006 American Society for Investigative Pathology

Mutant Fibrinogen Cleared from the Endoplasmic Reticulum via Endoplasmic Reticulum-Associated Protein Degradation and Autophagy

An Explanation for Liver Disease

Kristina B. Kruse^*, Amy Dear, Erin R. Kaltenbrun^*, Brandan E. Crum^*, Peter M. George, Stephen O. Brennan and Ardythe A. McCracken^*

From the Biology Department,^* University of Nevada, Reno, Nevada; and the Molecular Pathology Lab, Christchurch School of Medicine and Health Sciences, University of Otago, Christchurch, New Zealand

The endoplasmic reticulum (ER) quality control processes recognize and remove aberrant proteins from the secretory pathway. Several variants of the plasma protein fibrinogen are recognized as aberrant and degraded by ER-associated protein degradation (ERAD), thus leading to hypofibrinogenemia. A subset of patients with hypofibrinogenemia exhibit hepatic ER accumulation of the variant fibrinogens and develop liver cirrhosis. One such variant named Aguadilla has a substitution of Arg375 to Trp in the -chain. To understand the cellular mechanisms behind clearance of the aberrant Aguadilla -chain, we expressed the mutant D domain in yeast and found that it was cleared from the ER via ERAD. In addition, we discovered that when ERAD was saturated, aggregated Aguadilla D accumulated within the ER while a soluble form of the polypeptide transited the secretory pathway to the trans-Golgi network where it was targeted to the vacuole for degradation. Examination of Aguadilla D in an autophagy-deficient yeast strain showed stabilization of the aggregated ER form, indicating that these aggregates are normally cleared from the ER via the autophagic pathway. These findings have clinical relevance in the understanding of and treatment for ER storage diseases.

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