Jung Ji-Ung, Ravi Sowndharya, Lee Dong W, McFadden Kassandra, Kamradt Michael L, Toussaint L Gerard, Sitcheran Raquel
Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, TX 77843-1114, USA.
Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, College Station, TX 77807-3260, USA; The Texas Brain and Spine Institute, Bryan, TX 77807, USA.
Curr Biol. 2016 Dec 19;26(24):3288-3302. doi: 10.1016/j.cub.2016.10.009. Epub 2016 Nov 23.
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.
尽管核因子κB诱导激酶（NIK）在免疫中的作用已得到充分证实，但其在癌症中的相关性才刚刚显现。在此，我们描述了NIK在调节线粒体动力学和运动性以促进细胞侵袭方面的新功能。我们发现，在癌细胞系、离体肿瘤组织和小鼠胚胎成纤维细胞（MEF）中，NIK定位于线粒体。NIK促进线粒体分裂、速度和定向迁移，导致线粒体在迁移细胞周边进行亚细胞分布。此外，NIK是Drp1募集到线粒体所必需的，它与Drp1形成复合物，并调节Drp1在Ser-616位点的磷酸化和在Ser-637位点的去磷酸化。与NIK在调节线粒体动力学中的作用一致，我们证明Drp1是NIK依赖性细胞因子诱导侵袭所必需的。重要的是，利用MEF，我们证明NIK信号通路已确定的下游介质IκB激酶α/β（IKKα/β）和核因子κB，对于NIK调节细胞侵袭、Drp1线粒体定位或线粒体分裂并非必需。我们的结果确立了一种不依赖IKK的NIK信号传导新范式，并显著扩展了当前认为NIK主要存在于细胞质中且仅调节核因子κB活性的观点。总体而言，这些发现突出了NIK在肿瘤发病机制中的重要性，并催生了通过抑制NIK和Drp1来减轻线粒体功能障碍的新治疗策略。
