PuSH - Publication Server of Helmholtz Zentrum München: Ring finger protein 11 inhibits melanocortin 3 and 4 receptor signaling.

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Müller, A.* ; Niederstadt, L.* ; Jonas, W.* ; Yi, C.X.* ; Meyer, F.* ; Wiedmer, P.* ; Fischer, J.* ; Grötzinger, C.* ; Schürmann, A.* ; Tschöp, M.H. ; Kleinau, G.* ; Grüters, A.* ; Krude, H.* ; Biebermann, H.*

Ring finger protein 11 inhibits melanocortin 3 and 4 receptor signaling.

Front. Endocrin. 7:109 (2016)

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Intact melanocortin signaling via the G protein-coupled receptors (GPCRs), melanocortin receptor 4 (MC4R), and melanocortin receptor 3 (MC3R) is crucial for body weight maintenance. So far, no connection between melanocortin signaling and hypothalamic inflammation has been reported. Using a bimolecular fluorescence complementation library screen, we identified a new interaction partner for these receptors, ring finger protein 11 (RNF11). RNF11 participates in the constitution of the A20 complex that is involved in reduction of tumor necrosis factor α (TNFα)-induced NFκB signaling, an important pathway in hypothalamic inflammation. Mice treated with high-fat diet (HFD) for 3 days demonstrated a trend toward an increase in hypothalamic Rnf11 expression, as shown for other inflammatory markers under HFD. Furthermore, Gs-mediated signaling of MC3/4R was demonstrated to be strongly reduced to 20-40% by co-expression of RNF11 despite unchanged total receptor expression. Cell surface expression was not affected for MC3R but resulted in a significant reduction of MC4R to 61% by co-expression with RNF11. Mechanisms linking HFD, inflammation, and metabolism remain partially understood. In this study, a new axis between signaling of specific body weight regulating GPCRs and factors involved in hypothalamic inflammation is suggested.

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