Dept. of Microbiology, The University of Iowa, 3-403 Bowen Science Building, 51 Newton Road, Iowa City, IA 52242, USA.
Medical Scientist Training Program, The University of Iowa, Carver College of Medicine, 2206 MERF, Iowa City, IA 52242-2600, USA.
Sci Rep. 2016 Oct 18;6:35349. doi: 10.1038/srep35349.
The adaptor protein TNF receptor-associated factor 3 (TRAF3) is a critical regulator of B lymphocyte survival. B cell-specific TRAF3 deficiency results in enhanced viability and is associated with development of lymphoma and multiple myeloma. We show that TRAF3 deficiency led to induction of two proteins important for glucose metabolism, Glut1 and Hexokinase 2 (HXK2). This was associated with increased glucose uptake. In the absence of TRAF3, anaerobic glycolysis and oxidative phosphorylation were increased in B cells without changes in mitochondrial mass or reactive oxygen species. Chemical inhibition of glucose metabolism or glucose deprivation substantially attenuated the enhanced survival of TRAF3-deficient B cells, with a decrease in the pro-survival protein Mcl-1. Changes in Glut1 and Mcl-1 levels, glucose uptake and B cell number in the absence of TRAF3 were all dependent upon NF-κB inducing kinase (NIK). These results indicate that TRAF3 deficiency suffices to metabolically reprogram B cells, a finding that improves our understanding of the role of TRAF3 as a tumor suppressor, and suggests potential therapeutic strategies.
衔接蛋白肿瘤坏死因子受体相关因子 3（TRAF3）是 B 淋巴细胞存活的关键调节因子。B 细胞特异性 TRAF3 缺乏会导致存活率提高，并与淋巴瘤和多发性骨髓瘤的发展相关。我们发现 TRAF3 缺乏会诱导两种对葡萄糖代谢很重要的蛋白，葡萄糖转运蛋白 1（Glut1）和己糖激酶 2（HXK2）。这与葡萄糖摄取的增加有关。在 TRAF3 缺乏的情况下，B 细胞的无氧糖酵解和氧化磷酸化增加，而线粒体质量或活性氧没有变化。葡萄糖代谢的化学抑制或葡萄糖剥夺显著减弱了 TRAF3 缺陷 B 细胞的存活，同时抗细胞凋亡蛋白 Mcl-1 减少。TRAF3 缺乏时 Glut1 和 Mcl-1 水平、葡萄糖摄取和 B 细胞数量的变化都依赖于 NF-κB 诱导激酶（NIK）。这些结果表明，TRAF3 缺乏足以使 B 细胞代谢重编程，这一发现提高了我们对 TRAF3 作为肿瘤抑制因子的作用的理解，并提示了潜在的治疗策略。
