Zrt/Irt-like protein (ZIP) family members typically mediate zinc transport into the cytoplasm. Here, we characterize SLC39A11(ZIP11)—an evolutionarily conserved ZIP homologous toEscherichia colimetal ZupT—revealing its context-dependent role in metal homeostasis. ZIP11 could remove Fe2+from the endoplasmic reticulum (ER)/Golgi to the cytosol when ER/Golgi Fe2+rises. This is relevant to fibrosis, where ZIP13 upregulation supports collagen synthesis and ZIP11 mitigates iron overload. Significantly, AAV8-mediated ZIP11 expression drastically suppresses CCl4-induced liver fibrosis in mice, highlighting therapeutic potential. However, ZIP11 normally regulates Mn2+partitioning between ER/Golgi and cytosol: its loss reduces ER/Golgi Mn2+, increases cytosolic Mn2+, and enhances manganese toxicity. ZIP11 and Mn2+transporter TMEM165 double deficiency exacerbates Mn2+sensitivity, indicating synergy between them. We therefore establish ZIP11 as an ER/Golgi Mn2+transporter with Fe2+transport plasticity and as an ER/Golgi-to-cytosol iron transporter that acts oppositely to ZIP13 to maintain optimal ER/Golgi iron levels.

Link:https://www.sciencedirect.com/science/article/pii/S2211124726008594