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DYMECLIN, THE PROTEIN DEFECTIVE IN DMC SYNDROME AND SMC DYSPLASIA IS AN EFFECTOR OF RAB33B INVOLVED IN GOLGI-ER TRAFFICKING
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International audience. DYMECLIN and RAB33B are two proteins involved in ER-Golgi trafficking whose genetic mutations have been associated respectively with Dyggve-Melchior-Clausen syndrome (DMC, MIM #223800) and Smith McCort dysplasia (SMC2, MIM #615222), two related skeletal diseases. Interestingly, some mutations in DYMECLIN can also cause SMC dysplasia (SMC1, MIM #607326) suggesting a functional link with RAB33B. Here, we show that the two proteins partially co-localize at the Golgi and physically interact in co-immunoprecipitation experiments. While downregulation of RAB33B resulted in DYMECLIN mislocalization, expression of the constitutively active form of the GTPase (RAB33B-Q92L) induced a strong recruitment of DYMECLIN at the Golgi. As RAB33B is known to act both as a regulator of autophagy initiation and as a COP-I-independent regulator of the Golgi-ER retrograde trafficking, we tested whether either function could be affected in the absence of DYMECLIN. We found that RAB33B-Q92L was still capable of inducing LC3-II in the absence of DYMECLIN, suggesting that DYMECLIN is not crucial in the autophagic function of RAB33B. By contrast, retrograde trafficking was impaired in DYMECLIN-deficient cells, as evidenced by Shiga toxin assays. These data suggest that DYMECLIN is an effector protein of RAB33B involved in Golgi-ER trafficking.
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