TY - JOUR T1 - ARL15 modulates magnesium homeostasis through N-glycosylation of CNNMs JF - bioRxiv DO - 10.1101/2020.09.09.289835 SP - 2020.09.09.289835 AU - Yevgen Zolotarov AU - Chao Ma AU - Irene González-Recio AU - Serge Hardy AU - Gijs Franken AU - Noriko Uetani AU - Femke Latta AU - Elie Kostantin AU - Jonathan Boulais AU - Marie-Pier Thibault AU - Jean-François Côté AU - Irene Díaz Moreno AU - Antonio Díaz Quintana AU - Joost G.J. Hoenderop AU - Luis Alfonso Martínez-Cruz AU - Michel L. Tremblay AU - Jeroen H.F. de Baaij Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/09/10/2020.09.09.289835.abstract N2 - Cyclin M (CNNM1-4) proteins maintain cellular and body magnesium (Mg2+) homeostasis. Using various biochemical approaches, we have identified members of the CNNM family as direct interacting partners of ADP-ribosylation factor-like protein 15 (ARL15), a small GTP-binding protein. ARL15 interacts with CNNMs at their carboxyl-terminal conserved cystathionine-β-synthase (CBS) domains. In silico modeling of the interaction using the reported structures of both CNNM2 and ARL15 supports that the small GTPase specifically binds the CBS1 domain. Immunocytochemical experiments demonstrate that CNNM2 and ARL15 co-localize in the kidney, with both proteins showing subcellular localization in the Golgi-apparatus. Most importantly, we found that ARL15 is required for forming complex N-glycosylation of CNNMs. Overexpression of ARL15 promotes complex N-glycosylation of CNNM3. Mg2+ uptake experiments with a stable isotope demonstrate that there is a significant increase of 25Mg2+ uptake upon knockdown of ARL15 in multiple kidney cancer cell lines. Altogether, our results establish ARL15 as a novel negative regulator of Mg2+ transport by promoting the complex N-glycosylation of CNNMs.Competing Interest StatementThe authors have declared no competing interest. ER -