RaIB GTPase-mediated activation of the IκB family kinase TBK1 couples innate immune signaling to tumor cell survival

The monomeric RaIGTPases, RaIA and RalB are recognized as components of a regulatory framework supporting tumorigenic transformation. Specifically, RaIB is required to suppress apoptotic checkpoint activation, the mechanistic basis of which is unknown. Reported effector proteins of RaIB include the Sec5 component of the exocyst, an octameric protein complex implicated in tethering of vesicles to membranes. Surprisingly, we find that the RaIB/Sec5 effector complex directly recruits and activates the atypical I kappa B 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 RaIGTPases to cancer cell survival and reveal the RaIB/Sec5 effector complex as a component of TBK1-dependent innate immune signaling.