RESUMEN

The monomeric RalGTPases, RalA and RalB are recognized as components of a regulatory framework supporting tumorigenic transformation. Specifically, RalB is required to suppress apoptotic checkpoint activation, the mechanistic basis of which is unknown. Reported effector proteins of RalB include the Sec5 component of the exocyst, an octameric protein complex implicated in tethering of vesicles to membranes. Surprisingly, we find that the RalB/Sec5 effector complex directly recruits and activates the atypical IkappaB kinase family member TBK1. In cancer cells, constitutive engagement of this pathway, via chronic RalB activation, restricts initiation of apoptotic programs typically engaged in the context of oncogenic stress. Although dispensable for survival in a nontumorigenic context, this pathway helps mount an innate immune response to virus exposure. These observations define the mechanistic contribution of RalGTPases to cancer cell survival and reveal the RalB/Sec5 effector complex as a component of TBK1-dependent innate immune signaling.

Asunto(s)

Proteínas Portadoras/metabolismo , Supervivencia Celular , Inmunidad Innata/fisiología , Neoplasias/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/fisiología , Proteínas de Unión al GTP ral/metabolismo , Animales , Apoptosis/fisiología , Proteínas Portadoras/genética , Transformación Celular Neoplásica , Activación Enzimática , Células HeLa , Humanos , Ratones , Ratones Noqueados , Complejos Multiproteicos , Proteínas Serina-Treonina Quinasas/genética , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Proteínas de Transporte Vesicular , Proteínas de Unión al GTP ral/genética