Iron Uptake Mediated by Binding of H-Ferritin to the TIM-2 Receptor in Mouse Cells

Abstract

Ferritin binds specifically and saturably to a variety of cell types, and recently several ferritin receptors have been cloned. TIM-2 is a specific receptor for H ferritin (HFt) in the mouse. TIM-2 is a member of the T cell immunoglobulin and mucin domain containing (TIM) protein family and plays an important role in immunity. The expression of TIM-2 outside of the immune system indicates that this receptor may have broader roles. We tested whether ferritin binding to TIM-2 can serve as an iron delivery mechanism. TIM-2 was transfected into normal (TCMK-1) mouse kidney cells, where it was appropriately expressed on the cell surface. HFt was labeled with 55Fe and 55Fe-HFt was incubated with TIM-2 positive cells or controls. 55Fe-HFt uptake was observed only in TIM-2 positive cells. HFt uptake was also seen in A20 B cells, which express endogenous TIM-2. TIM-2 levels were not increased by iron chelation. Uptake of 55Fe-HFt was specific and temperature-dependent. HFt taken up by TIM-2 positive cells transited through the endosome and eventually entered a lysosomal compartment, distinguishing the HFt pathway from that of transferrin, the classical vehicle for cellular iron delivery. Iron delivered following binding of HFt to TIM-2 entered the cytosol and became metabolically available, resulting in increased levels of endogenous intracellular ferritin. We conclude that TIM-2 can function as an iron uptake pathway.

Prion protein functions as a ferrireductase partner for ZIP14 and DMT1

“…To evaluate whether PrP C influences the uptake and storage of an alternative source of iron that does not require the activity of FR proteins, uptake of 59 Fe from intra-peritoneally introduced 59 Fe-ferritin was evaluated since ferritin is endocytosed by the Tim-2 receptor before the release of associated 59 Fe in the cytosol [30]. …”

“…Uptake of 59 Fe-Tf by the spleen and bone marrow, main hematopoietic organs that utilize Tf-bound iron, and 59 Fe-NTBI by the liver and pancreas, principal organs that store and utilize NTBI, was significantly lower in PrP −/− mice relative to PrP +/+ controls despite systemic iron over load [28]. On the other hand, uptake, storage, and utilization of 59 Fe from iron-loaded ferritin that utilizes receptor-mediated uptake pathway [30] was increased in PrP −/− mice, highlighting the iron-deficiency of these mice, and implicating PrP C in the uptake of ferric iron, not ferritin iron that is stored and used effectively in its absence. It is likely that the relatively mild iron deficiency in PrP −/− mice is due to the participation of PrP C in the uptake of mainly NTBI from the plasma membrane, not Tf-iron that can utilize alternative FR proteins such as Steap3 in late endosomes.…”

The relationship between iron dyshomeostasis and amyloidogenesis in Alzheimer's disease: Two sides of the same coin

“…5a). Tim2 bound ferritin endocytosis is followed by lysosomal degredation and elevated endogenous ferritin synthesis 215 . Tim2 acts as the iron uptake pathway for oligodendrocytes and is integral to oligodendrocye health and iron regulation.…”

“…A ) Tim2 facilitates ferritin endocytosis and iron release via lysosomal degradation 215 . B ) Normal breakdown and dysfunction of myelin with age releases iron and impairs trophic support 248 .…”

Endocytic pathway of exogenous iron-loaded ferritin in intestinal epithelial (Caco-2) cells

“…The T cell immunoglobulin and mucin domain-2 (TIM-2) receptor binds H-ferritin, allowing for its entry into endosomes (5,11). TIM-2 expression is restricted to mouse B lymphocytes, embryonic liver, and kidney mouse cells, and to rat oligodendrocytes (5,55).…”