Fe²⁺ Triggers Endocytosis of Carrier Proteins in Mammalian Cells.

Abstract

Human serum albumin (HSA) plays an indispensable role as a carrier of endogenous and exogenous substances in vivo. The efficiency of endocytosis determines the transport capacity. However, the potential for enhancing the efficiency of HSA endocytosis remains largely unknown. This research represented a substantial advancement, revealing that Fe²⁺ markedly increased HSA endocytosis. Moreover, Fe²⁺ facilitated the endocytosis and transport of HSA in vivo. The enhancement in HSA uptake facilitated by Fe²⁺ is markedly decreased following iron chelation, indicating a specific interaction between Fe²⁺ and HSA that promoted endocytosis. Moreover, the study elucidated that FcRn and caveolin regulated HSA endocytosis under normal conditions. Yet, in the presence of Fe²⁺, endocytosis shifted toward clathrin- and caveolin-enriched membrane domains, requiring both divalent metal transporter 1 (DMT1) and FcRn for efficient process completion. Thereby a new pathway is discovered for Fe²⁺-dependent HSA endocytosis involving DMT1 and clathrin. This findings highlighted the crucial role of iron in enhancing HSA endocytosis and transport, establishing Fe²⁺ as a vital endocytic enhancer that required binding to HSA to substantially improve its uptake. This insight into the mechanism of HSA endocytosis not only expands the understanding of protein transport but also opens new avenues for therapeutic intervention.