NIK/MAP3K14 Regulates Mitochondrial Dynamics and Trafficking to Promote Cell Invasion

Although the role of NF-κB-inducing kinase (NIK) in immunity is well established, its relevance in cancer is just emerging. Here we describe novel functions for NIK in regulating mitochondrial dynamics and motility to promote cell invasion. We show that NIK is localized to mitochondria in cancer cell lines, ex vivo tumor tissue, and mouse embryonic fibroblasts (MEFs). NIK promotes mitochondrial fission, velocity, and directional migration, resulting in subcellular distribution of mitochondria to the periphery of migrating cells. Moreover, NIK is required for recruitment of Drp1 to mitochondria, forms a complex with Drp1, and regulates Drp1 phosphorylation at Ser-616 and dephosphorylation at Ser-637. Consistent with a role for NIK in regulating mitochondrial dynamics, we demonstrate that Drp1 is required for NIK-dependent, cytokine-induced invasion. Importantly, using MEFs, we demonstrate that the established downstream mediators of NIK signaling, IκB kinase α/β (IKKα/β) and NF-κB, are not required for NIK to regulate cell invasion, Drp1 mitochondrial localization, or mitochondrial fission. Our results establish a new paradigm for IKK-independent NIK signaling and significantly expand the current dogma that NIK is predominantly cytosolic and exclusively regulates NF-κB activity. Overall, these findings highlight the importance of NIK in tumor pathogenesis and invite new therapeutic strategies that attenuate mitochondrial dysfunction through inhibition of NIK and Drp1. [Display omitted] •NIK localizes to mitochondria in MEFs, cancer cell lines, and ex vivo tumor tissue•NIK regulates mitochondrial velocity and anterograde movement to the cell periphery•NIK enhances fission, Drp1 phosphorylation, and Drp1 mitochondrial localization•NIK regulates invasion and mitochondrial dynamics independent of IKK/NF-κB Jung et al. identify novel functions of NIK in regulating mitochondrial dynamics and tumor cell invasion through control of Drp1 phosphorylation and mitochondrial trafficking to the leading edge of migrating cells. These properties do not require NIK’s downstream targets, IKKα/β, establishing a new paradigm for NIK signaling in mitochondria.