The Retromer Complex Protein VPS35 Modulates Iron Homeostasis by Regulating Hepcidin-Induced Ferroportin Degradation

Abstract

Hepcidin-mediated degradation of the iron exporter Ferroportin is an essential mechanism for iron homeostasis. Upon Hepcidin binding to the Ferroportin receptor at the cell surface, Ferroportin is rapidly internalized and degraded. However, the underlying mechanism for the degradation has not been uncovered. Using a functional genomics approach, VPS35, a member of the Retromer Complex, is identified as an important regulator for Hepcidin-induced Ferroportin degradation. Cells with CRISPR-induced mutation in VPS35 demonstrated significantly reduced Ferroportin degradation in the presence of Hepcidin. Interestingly, VPS35 mutations and dysfunction of other members of the Retromer Complex have been associated with familial autosomal-dominant Parkinson’s disease, a progressive neurodegenerative disease with well-established iron accumulation phenotype. The result of this study reveals a previously unappreciated role for the Retromer Complex in the regulation of iron homeostasis.