Research Center for Asian Infectious Diseases, The Institute of Medical Science, The University of Tokyo.
Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences.
Proc Jpn Acad Ser B Phys Biol Sci. 2021;97(4):145-160. doi: 10.2183/pjab.97.009.
NF-κB was first identified in 1986 as a B cell-specific transcription factor inducing immunoglobulin κ light chain expression. Subsequent studies revealed that NF-κB plays important roles in development, organogenesis, immunity, inflammation, and neurological functions by spatiotemporally regulating cell proliferation, differentiation, and apoptosis in several cell types. Furthermore, studies on the signal pathways that activate NF-κB led to the discovery of TRAF family proteins with E3 ubiquitin ligase activity, which function downstream of the receptor. This discovery led to the proposal of an entirely new signaling mechanism concept, wherein K63-ubiquitin chains act as a scaffold for the signaling complex to activate downstream kinases. This concept has revolutionized ubiquitin studies by revealing the importance of the nonproteolytic functions of ubiquitin not only in NF-κB signaling but also in a variety of other biological systems. TRAF6 is the most diverged among the TRAF family proteins, and our studies uncovered its notable physiological and pathological functions.
NF-κB 于 1986 年首次被鉴定为一种 B 细胞特异性转录因子，可诱导免疫球蛋白 κ 轻链表达。随后的研究表明，NF-κB 通过时空调节几种细胞类型的细胞增殖、分化和凋亡，在发育、器官发生、免疫、炎症和神经功能中发挥重要作用。此外，对激活 NF-κB 的信号通路的研究导致发现了具有 E3 泛素连接酶活性的 TRAF 家族蛋白，它们作为受体下游的功能蛋白。这一发现提出了一个全新的信号机制概念，其中 K63-泛素链作为信号复合物的支架，激活下游激酶。这一概念通过揭示泛素的非蛋白水解功能不仅在 NF-κB 信号转导中，而且在各种其他生物系统中的重要性，彻底改变了泛素研究。TRAF6 是 TRAF 家族蛋白中分化最明显的一种，我们的研究揭示了其显著的生理和病理功能。
