Lee Yeojin, Lee In Young, Yun Hee Jae, Lee Woo Sang, Kang Seongman, Cho Ssang-Goo, Lee Ji Eun, Choi Eui-Ju
Department of Life Sciences, Korea University, Seoul 136-701, South Korea.
Department of Animal Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul 143-701, South Korea.
Biochem Biophys Res Commun. 2016 Sep 16;478(2):784-90. doi: 10.1016/j.bbrc.2016.08.025. Epub 2016 Aug 5.
TNF receptor-associated factor 6 (TRAF6) plays a critical role in NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways, both of which mediate macrophage activation in response to pathogen-associated molecular patterns such as bacterial endotoxin, lipopolysaccharides (LPS). In this study, we investigated whether HLA-B associated transcript-3 (BAT3) regulates LPS-induced macrophage activation. BAT3 physically interacted with TRAF6 in macrophages, and this interaction was enhanced in the cells after LPS treatment. Furthermore, BAT3 inhibited the homo-oligomerization of TRAF6 as well as the interaction between TRAF6 and its downstream kinase transforming growth factor beta-activated kinase 1 (TAK1), thereby suppressing TRAF6-mediated signaling events. Intriguingly, TRAF6 mediated ubiquitination of BAT3 and this ubiquitination was crucial for its inhibitory effect on TRAF6-mediated signaling. Depletion of BAT3 by RNA interference resulted in enhancement of LPS-induced activation of the NF-κB signaling with increasing expression levels of pro-inflammatory cytokines. These findings suggest that BAT3 functions as the negative regulator of LPS-induced macrophage activation.
肿瘤坏死因子受体相关因子6（TRAF6）在核因子κB（NF-κB）和丝裂原活化蛋白激酶（MAPK）信号通路中起关键作用，这两条信号通路均可介导巨噬细胞对诸如细菌内毒素、脂多糖（LPS）等病原体相关分子模式产生应答而被激活。在本研究中，我们探究了HLA-B相关转录本3（BAT3）是否调节LPS诱导的巨噬细胞激活。BAT3在巨噬细胞中与TRAF6发生物理相互作用，且这种相互作用在LPS处理后的细胞中增强。此外，BAT3抑制TRAF6的同源寡聚化以及TRAF6与其下游激酶转化生长因子β激活激酶1（TAK1）之间的相互作用，从而抑制TRAF6介导的信号转导事件。有趣的是，TRAF6介导BAT3的泛素化，且这种泛素化对其对TRAF6介导信号的抑制作用至关重要。通过RNA干扰使BAT3缺失导致LPS诱导的NF-κB信号激活增强，促炎细胞因子表达水平增加。这些发现表明，BAT3作为LPS诱导的巨噬细胞激活的负调节因子发挥作用。
