J Biol Chem

. 2024 May 6:107348.

doi: 10.1016/j.jbc.2024.107348. Online ahead of print.

Calcium and IL-6 regulate the anterograde trafficking and plasma membrane residence of the iron exporter ferroportin to modulate iron efflux

Shaina L Rosenblum ¹, Danielle K Bailey ¹, Daniel J Kosman ²

Affiliations expand

• PMID: 38718866

DOI: 10.1016/j.jbc.2024.107348

Abstract

Iron is an essential element for proper cell functioning, but unbalanced levels can cause cell death. Iron metabolism is controlled at the blood-tissue barriers provided by microvascular endothelial cells. Dysregulated iron metabolism at these barriers is a factor in both neurodegenerative and cardiovascular diseases. Mammalian iron efflux is mediated by the iron efflux transporter ferroportin (Fpn). Inflammation is a factor in many diseases and correlates with increased tissue iron accumulation. Evidence suggests treatment with IL-6 increases intracellular calcium levels and calcium is known to play an important role in protein trafficking. We have shown that calcium increases plasma membrane localization of the iron uptake proteins ZIP8 and ZIP14, but if and how calcium modulates Fpn trafficking is unknown. In this article we examined the effects of IL-6 and calcium on Fpn localization to the plasma membrane. In HEK cells expressing a doxycycline-inducible GFP-tagged Fpn, calcium increased Fpn-GFP membrane presence by 2h, while IL-6 increased membrane-localized Fpn-GFP by 3h. Calcium pre-treatment increased Fpn-GFP mediated ⁵⁵Fe efflux from cells. ER calcium stores were shown to be important for Fpn-GFP localization and iron efflux. Use of calmodulin pathway inhibitors showed that calcium signaling is important for IL-6 induced Fpn relocalization. Studies in brain microvascular endothelial cells in transwell culture demonstrated an initial increase in ⁵⁵Fe flux with IL-6 that is reduced by 6 h coinciding with upregulation of hepcidin. Overall, this research details one pathway by which inflammatory signaling mediated by calcium can regulate iron metabolism, likely contributing to inflammatory disease mechanisms.

This paper is IMO important in understanding how our organs accumulate extra iron because of inflammation. In conclusion, Kosman says: " Overall, our data contributes to the connection between inflammatory processes and cellular iron metabolism, while shedding light on a new mechanism for Fpn regulation".

This is not an "easy" paper, at least for me. Here you can find the original article: https://www.jbc.org/article/S0021-9258(24)01849-0/fulltext

Perhaps you remember Prof. Kosman from his earlier papers and one poster with ATH434. In the poster, he demonstrated that ATH434 is safer iron chelator than the ones usually used and which did not work in PD.