The cysteine protease legumain is upregulated by vitamin D and regulates vitamin D metabolism

Forbord, Karl Martin, Okla, Meshail, Lunde, Ngoc Nguyen, Bosnjak, Tatjana, Arnekleiv, Guro, Hesselson, Daniel, Johansen, Harald Thidemann, Tang, Jonathan C. Y. ORCID:, Kassem, Moustapha, Solberg, Rigmor and Jafari, Abbas (2024) The cysteine protease legumain is upregulated by vitamin D and regulates vitamin D metabolism. Cells, 13 (1). ISSN 2073-4409

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Legumain is a lysosomal cysteine protease that has been implicated in an increasing amount of physiological and pathophysiological processes. However, the upstream mechanisms regulating the expression and function of legumain are not well understood. Here, we provide in vitro and in vivo data showing that vitamin D 3 (VD 3) enhances legumain expression and function. In turn, legumain alters VD 3 bioavailability, possibly through proteolytic cleavage of vitamin D binding protein (VDBP). Active VD 3 (1,25(OH) 2D 3) increased legumain expression, activity, and secretion in osteogenic cultures of human bone marrow stromal cells. Upregulation of legumain was also observed in vivo, evidenced by increased legumain mRNA in the liver and spleen, as well as increased legumain activity in kidneys from wild-type mice treated with 25(OH)D 3 (50 µg/kg, subcutaneously) for 8 days compared to a control. In addition, the serum level of legumain was also increased. We further showed that active legumain cleaved purified VDBP (55 kDa) in vitro, forming a 45 kDa fragment. In vivo, no VDBP cleavage was found in kidneys or liver from legumain-deficient mice (Lgmn −/−), whereas VDBP was cleaved in wild-type control mice (Lgmn +/+). Finally, legumain deficiency resulted in increased plasma levels of 25(OH)D 3 and total VD 3 and altered expression of key renal enzymes involved in VD 3 metabolism (CYP24A1 and CYP27B1). In conclusion, a regulatory interplay between VD 3 and legumain is suggested.

Item Type: Article
Additional Information: Funding Information: This work was supported by the Olav Thon Foundation and the University of Oslo, Norway; University of Copenhagen, Odense University Hospital, and University of Southern Denmark, Denmark; Garvan Institute of Medical Research and St. Vincent’s Clinical School, Sydney, Australia; Gerda og Aage Haenschs Fond, Direktør Michael Hermann Nielsens mindelegat, Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis’ Legat; and The Norwegian Pharmaceutical Society.
Uncontrolled Keywords: asparaginyl endopeptidase,legumain,metabolism,proteolysis,vitamin d,biochemistry, genetics and molecular biology(all),sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1300
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Musculoskeletal Medicine
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Depositing User: LivePure Connector
Date Deposited: 22 Dec 2023 02:22
Last Modified: 23 Jan 2024 01:39
DOI: 10.3390/cells13010036


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