Dion Sébastien P, Désilets Antoine, Lemieux Gabriel, Leduc Richard
Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada.
Institut de Pharmacologie de Sherbrooke, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada.
PLoS One. 2022 Aug 31;17(8):e0273825. doi: 10.1371/journal.pone.0273825. eCollection 2022.
TMPRSS6 is a type II transmembrane serine protease involved in iron homeostasis expressed as 4 isoforms in humans. TMPRSS6 isoform 2 downregulates hepcidin production by cleaving hemojuvelin and other surface proteins of hepatocytes. The functions of catalytically impaired isoforms 3 and 4 are still unknown. Here we demonstrate that TMPRSS6 isoforms 3 and 4 reduce the proteolytic activity of isoform 2 and uncover the ability of isoforms to interact. Moreover, we identified 49 potential protein partners common to TMPRSS6 isoforms, including TfR1, known to be involved in iron regulation. By co-expressing TMPRSS6 and TfR1, we show that TfR1 is cleaved and shed from the cell surface. Further, we demonstrate that TMPRSS6 isoforms 3 and 4 behave as dominant negative.
TMPRSS6是一种参与铁稳态的II型跨膜丝氨酸蛋白酶，在人类中以4种异构体形式表达。TMPRSS6异构体2通过切割血色素沉着症相关蛋白和肝细胞的其他表面蛋白来下调铁调素的产生。催化受损的异构体3和4的功能仍然未知。在这里，我们证明TMPRSS6异构体3和4降低了异构体2的蛋白水解活性，并揭示了异构体之间相互作用的能力。此外，我们鉴定出了TMPRSS6异构体共有的49个潜在蛋白质伴侣，包括已知参与铁调节的转铁蛋白受体1（TfR1）。通过共表达TMPRSS6和TfR1，我们表明TfR1被切割并从细胞表面脱落。此外，我们证明TMPRSS6异构体3和4表现为显性负性。
