Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, 510060, Guangzhou, Guangdong, China.
Department of Pathogen Biology and Immunology, School of Basic Course, Guangdong Pharmaceutical University, 510006, Guangzhou, Guangdong, China.
Nat Commun. 2018 Oct 22;9(1):4381. doi: 10.1038/s41467-018-06756-3.
Maintaining innate immune homeostasis is important for individual health. Npl4 zinc finger (NZF) domain-mediated ubiquitin chain sensing is reported to function in the nuclear factor-kappa B (NF-κB) signal pathway, but the regulatory mechanism remains elusive. Here we show that cyclophilin J (CYPJ), a member of the peptidylprolyl isomerase family, is induced by inflammation. CYPJ interacts with the NZF domain of transform growth factor-β activated kinase 1 binding protein 2 and 3 as well as components of the linear ubiquitin chain assembly complex to block the binding of ubiquitin-chain and negatively regulates NF-κB signaling. Mice with Cypj deficiency are susceptible to lipopolysaccharide and heat-killed Listeria monocytogenes-induced sepsis and dextran sulfate sodium-induced colitis. These findings identify CYPJ as a negative feedback regulator of the NF-κB signaling pathway, and provide insights for understanding the homeostasis of innate immunity.
维持固有免疫稳态对于个体健康很重要。现已报道，Npl4 锌指（NZF）结构域介导的泛素链感应在核因子-κB（NF-κB）信号通路中发挥作用，但调控机制尚不清楚。本研究显示，亲环素 J（CYPJ）是肽基脯氨酰顺反异构酶家族的一员，可被炎症诱导。CYPJ 与转化生长因子-β激活激酶 1 结合蛋白 2 和 3 的 NZF 结构域以及线性泛素链组装复合物的成分相互作用，阻断泛素链的结合，从而负调控 NF-κB 信号。Cypj 缺陷小鼠易发生脂多糖和热灭活李斯特菌单核细胞增生李斯特菌诱导的败血症和葡聚糖硫酸钠诱导的结肠炎。这些发现表明 CYPJ 是 NF-κB 信号通路的负反馈调节剂，为理解固有免疫的稳态提供了新的见解。
