β‐Glucosylceramide: a novel method for enhancement of natural killer T lymphoycte plasticity in murine models of immune‐mediated disorders

BACKGROUND: β‐Glucosylceramide, a naturally occurring glycolipid, exerts modulatory effects on natural killer T (NKT) lymphocytes. AIM: To determine whether β‐glucosylceramide can alter NKT function in opposite directions, colitis was induced by intracolonic installation of trinitrobenzenesulphonic acid, and hepatocellular carcinoma (HCC) was induced by transplantation of Hep3B cells. METHODS: The immunological effect of β‐glucosylceramide was assessed by analysis of intrahepatic and intrasplenic lymphocyte populations, serum cytokines and STAT protein expression. RESULTS: Administration of β‐glucosylceramide led to alleviation of colitis and to suppression of HCC, manifested by improved survival and decreased tumour volume. The beneficial effects were associated with an opposite immunological effect in the two models: the peripheral:intrahepatic CD4:CD8 lymphocyte ratio increased in the colitis model and decreased in the HCC group. The peripheral:intrahepatic NKT lymphocyte ratio decreased in β‐glucosylceramide‐treated mice solely in the HCC model. The effect of β‐glucosylceramide was associated with decreased STAT1 and 4 expression, and with overexpression of STAT6, along with decreased interferon γ levels in the colitis model, whereas an opposite effect was noted in the HCC model. CONCLUSIONS: β‐glucosylceramide alleviates immunologically incongruous disorders and may be associated with “fine tuning” of immune responses, by changes in plasticity of NKT lymphocytes

B Physics at LEP

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ARL15 modulates magnesium homeostasis through N-glycosylation of CNNMs.

Cyclin M (CNNM1-4) proteins maintain cellular and body magnesium (Mg(2+)) homeostasis. Using various biochemical approaches, we have identified members of the CNNM family as direct interacting partners of ADP-ribosylation factor-like GTPase 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 between CNNM2 and ARL15 supports that the small GTPase specifically binds the CBS1 and CNBH domains. Immunocytochemical experiments demonstrate that CNNM2 and ARL15 co-localize in the kidney, with both proteins showing subcellular localization in the endoplasmic reticulum, Golgi apparatus and the plasma membrane. Most importantly, we found that ARL15 is required for forming complex N-glycosylation of CNNMs. Overexpression of ARL15 promotes complex N-glycosylation of CNNM3. Mg(2+) uptake experiments with a stable isotope demonstrate that there is a significant increase of (25)Mg(2+) uptake upon knockdown of ARL15 in multiple kidney cancer cell lines. Altogether, our results establish ARL15 as a novel negative regulator of Mg(2+) transport by promoting the complex N-glycosylation of CNNMs