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| 1 | Preventing abnormal NF-κB activation and autoimmunity by Otub1-mediated p100 stabilization显示文摘NF-κB, a family of transcription factors regulating diverse biological processes including immune responses, is activated by canonical and noncanonical pathways based on degradation of IκBα and processing of the IκB-like protein p100, respectively. Although p100 responds to noncanonical NF-κB stimuli for processing, it does not undergo degradation, but rather becomes accumulated, along with canonical NF-κB activation. We show here that the stability of p100 is tightly controlled by a deubiquitinase, Otub1. Otub1 deficiency not only promotes signal-induced p100 processing and noncanonical NF-κB activation but also causes steady-state p100 degradation, leading to aberrant NF-κB activation in the canonical pathway. B-cell-conditional deletion of Otub1 results in B-cell hyperplasia, antibody hyper-production, and lupus-like autoimmunity. Otub1-deficient B cells display aberrantly activated phenotypes and overproduce the cytokine IL-6, contributing to autoimmunity induction. Thus, maintenance of p100 stability by Otub1 serves as an unusual mechanism of NF-κB regulation that prevents autoimmunity. | Yanchuan Li Jin-Young Yang Xiaoping Xie Zuliang Jie Lingyun Zhang Jianhong Shi Daniel Lin Meidi Gu Xiaofei Zhou Haiyan S. Li Stephanie S. Watowich Antrix Jain Sung Yun Jung Jun Qin Xuhong Cheng Shao-Cong Sun | 2019 | Cell Research2019，29，6： | 3 |
| 2 | Lymphatic endothelial cells regulate B-cell homing to lymph nodes via a NIK-dependent mechanism显示文摘B cells home to the lymph nodes(LNs)via high endothelial venules(HEVs)under the guidance of chemokines,particularly CXCL13.However,as CXCL13 is not directly made in HEVs,the molecular mechanism mediating B-cell homing to LNs has remained unclear.We show here that nuclear factor(NF)-κB-inducing kinase(NIK),a kinase mediating activation of the noncanonical NF-κB pathway,functions in lymphatic endothelial cells(LECs)to regulate B-cell homing to LNs.LEC-conditional deletion of NIK in mice did not affect the integrity or global function of lymphatic vessels but caused a severe reduction in the frequency of B cells in LNs.The LEC-specific NIK deficiency did not affect the survival of B cells or the frequency of B cells in the spleen.B-cell adoptive transfer studies revealed that the LEC-specific NIK deletion impairs the ability of LNs to recruit B cells.We further show that NIK mediates expression of the chemokines CXCL13 and CCL19 in LECs.Although CCL19 is also expressed in blood endothelial cells(BECs),CXCL13 is not produced in BECs.These results suggest that NIK regulates naive B-cell homing to LNs via mediating production of the B-cell homing chemokine CXCL13 in LECs. | Jie Yang Siya Zhang Lingyun Zhang Xiaoping Xie Hui Wang Zuliang Jie Meidi Gu Jin-Young Yang Xuhong Cheng Shao-Cong Sun | 2019 | Cellular & Molecular Immunology2019，16，2： | 1 |
| 3 | TRAF2 regulates T cell immunity by maintaining a Tpl2-ERK survival signaling axis in effector and memory CD8 T cells显示文摘Generation and maintenance of antigen-specific effector and memory T cells are central events in immune responses against infections.We show that TNF receptor-associated factor 2(TRAF2)maintains a survival signaling axis in effector and memory CD8 T cells required for immune responses against infections.This signaling axis involves activation of Tpl2 and its downstream kinase ERK by NF-κB-inducing kinase(NIK)and degradation of the proapoptotic factor Bim.NIK mediates Tpl2 activation by stimulating the phosphorylation and degradation of the Tpl2 inhibitor p105.Interestingly,while NIK is required for Tpl2-ERK signaling under normal conditions,uncontrolled NIK activation due to loss of its negative regulator,TRAF2,causes constitutive degradation of p105 and Tpl2,leading to severe defects in ERK activation and effector/memory CD8 T cell survival.Thus,TRAF2 controls a previously unappreciated signaling axis mediating effector/memory CD8 T cell survival and protective immunity. | Xiaoping Xie Lele Zhu Zuliang Jie Yanchuan Li Meidi Gu Xiaofei Zhou Hui Wang Jae-Hoon Chang Chun-Jung Ko Xuhong Cheng Shao-Cong Sun | 2021 | Cellular & Molecular Immunology2021，18，9： | 0 |
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