Shengyi Iris Sun, PhD
Conformational diseases, such as certain liver disorders, cancers, and neurodegenerative diseases, are caused by proteins that fold incorrectly and aggregate together, disrupting cell functions. These conditions can occur when the cellular quality control systems fail to clear or repair these faulty proteins.
In a recent study published in Nature Communications, researchers at the University of Virginia School of Medicine led by Shengyi Iris Sun, PhD, an associate professor in the Department of Pharmacology, uncovered how one of these quality control systems, called the ER-associated degradation (ERAD) pathway, helps regulate the production and breakdown of fibrinogen, a key protein involved in blood clotting. They identified the SEL1L-HRD1 complex within the ERAD pathway as crucial for preventing a rare liver disorder, known as hepatic fibrinogen storage disease (HFSD).
HFSD occurs when fibrinogen cannot be properly released from the liver, leading to its buildup inside liver cells and low fibrinogen levels in the bloodstream. Until now, the detailed process behind fibrinogen production and disposal in liver cells has remained largely unknown.
The researchers showed that when the SEL1L-HRD1 complex is deficient in liver cells, it leads to the formation of abnormal fibrinogen retention and deposits. They further revealed that the SEL1L-HRD1 ERAD complex mediates the breakdown misfolded fibrinogen protein components, allowing only correctly folded fibrinogen to form.
“Our findings highlight the importance of SEL1L-HRD1 in maintaining normal fibrinogen production,” said Dr. Sun. “By clearing misfolded fibrinogen, this complex supports the healthy formation and release of this essential protein.”
The study also points to the SEL1L-HRD1 complex as a potential therapeutic target, as it helps reduce harmful effects of specific fibrinogen mutations that cause disease. This research provides new insights into both fibrinogen production and broader protein- conformational diseases, paving the way for future treatments.
Filed Under: Research