Sailland Juliette, Tribollet Violaine, Forcet Christelle, Billon Cyrielle, Barenton Bruno, Carnesecchi Julie, Bachmann Alice, Gauthier Karine Cécile, Yu Shan, Giguère Vincent, Chan Franky L, Vanacker Jean-Marc
Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, CNRS, Ecole Normale Supérieure de Lyon, 69007 Lyon, France;
Cancer and Inflammation Program, School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China; and.
Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):15108-13. doi: 10.1073/pnas.1402094111. Epub 2014 Oct 6.
Several physiopathological processes require orientated cellular migration. This phenomenon highly depends on members of the RHO family of GTPases. Both excessive and deficient RHO activity impair directional migration. A tight control is thus exerted on these proteins through the regulation of their activation and of their stability. Here we show that the estrogen-related receptor α (ERRα) directly activates the expression of TNFAIP1, the product of which [BTB/POZ domain-containing adapter for Cullin3-mediated RhoA degradation 2 (BACURD2)] regulates RHOA protein turnover. Inactivation of the receptor leads to enhanced RHOA stability and activation. This results in cell disorientation, increased actin network, and inability to form a lamellipodium at the migration edge. As a consequence, directional migration, but not cell motility per se, is impaired in the absence of the receptor, under pathological as well as physiological conditions. Altogether, our results show that the control exerted by ERRα on RHOA stability is required for directional migration.
几种生理病理过程需要定向细胞迁移。这种现象高度依赖于GTP酶RHO家族的成员。RHO活性过高或过低都会损害定向迁移。因此，通过调节这些蛋白质的激活和稳定性，对它们进行了严格的控制。在这里，我们表明雌激素相关受体α（ERRα）直接激活TNFAIP1的表达，其产物[含BTB/POZ结构域的Cullin3介导的RhoA降解衔接蛋白2（BACURD2）]调节RHOA蛋白周转。受体失活导致RHOA稳定性和激活增强。这导致细胞方向紊乱、肌动蛋白网络增加，并且在迁移边缘无法形成片状伪足。因此，在病理和生理条件下，缺乏该受体时，定向迁移会受损，但细胞运动本身不受影响。总之，我们的结果表明，ERRα对RHOA稳定性的控制是定向迁移所必需的。
