Type I interferon enhances necroptosis of Salmonella Typhimurium-infected macrophages by impairing antioxidative stress responses.
Type I interferon enhances necroptosis of Salmonella Typhimurium-infected macrophages by impairing antioxidative stress responses.
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DOI：
10.1083/jcb.201701107
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发表时间：
2017-12-04
期刊：
影响因子：
--
通讯作者：
Robinson N
中科院分区：
文献类型：
--
作者：
Hos NJ;Ganesan R;Gutiérrez S;Hos D;Klimek J;Abdullah Z;Krönke M;Robinson N
I型干扰素（IFN-I）触发感染链球菌的巨噬细胞坏死性凋亡。鼠伤寒沙门氏菌通过一个不清楚的机制。Hos等现在证明，RIP 3增强了Nrf 2与Pgam 5在S. Typhimurium感染的巨噬细胞，其减弱Nrf 2依赖性细胞保护途径并增加细胞死亡。鼠伤寒沙门氏菌利用宿主的I型干扰素（IFN-I）反应诱导巨噬细胞中受体相互作用蛋白（RIP）激酶介导的坏死性凋亡。然而，驱动IFN-I和RIP信号传导下游的坏死性凋亡执行的事件仍然难以捉摸。在这项研究中，我们证明了S。鼠伤寒感染通过RIP 3引起IFN-1介导的线粒体磷酸酶Pgam 5的上调。Pgam 5随后与Nrf 2相互作用，其在胞质溶胶中螯合Nrf 2，从而抑制Nrf 2依赖性抗氧化基因的转录。对S. Typhimurium诱导的氧化应激导致活性氧介导的线粒体损伤、能量消耗、自噬的瞬时诱导和p62的自噬降解。p62水平的降低削弱了p62与Keap 1的相互作用，这进一步降低了Nrf 2的功能和对S.鼠伤寒杆菌感染，最终导致细胞死亡。总的来说，我们确定受损的Nrf 2依赖的氧化还原稳态作为一个重要的机制，促进细胞死亡下游的IFN-Ⅰ和RIP 3信号在S。Typhimurium感染的巨噬细胞
Type I interferon (IFN-I) triggers necroptosis in macrophages infected with S. Typhimurium by an unclear mechanism. Hos et al. now demonstrate that RIP3 enhances the interaction of Nrf2 with Pgam5 in response to IFN-I signaling in S. Typhimurium–infected macrophages, which abates Nrf2-dependent cytoprotective pathways and increases cell death. Salmonella enterica serovar Typhimurium exploits the host’s type I interferon (IFN-I) response to induce receptor-interacting protein (RIP) kinase–mediated necroptosis in macrophages. However, the events that drive necroptosis execution downstream of IFN-I and RIP signaling remain elusive. In this study, we demonstrate that S. Typhimurium infection causes IFN-I–mediated up-regulation of the mitochondrial phosphatase Pgam5 through RIP3. Pgam5 subsequently interacts with Nrf2, which sequesters Nrf2 in the cytosol, thereby repressing the transcription of Nrf2-dependent antioxidative genes. The impaired ability to respond to S. Typhimurium–induced oxidative stress results in reactive oxygen species–mediated mitochondrial damage, energy depletion, transient induction of autophagy, and autophagic degradation of p62. Reduced p62 levels impair interaction of p62 with Keap1, which further decreases Nrf2 function and antioxidative responses to S. Typhimurium infection, eventually leading to cell death. Collectively, we identify impaired Nrf2-dependent redox homeostasis as an important mechanism that promotes cell death downstream of IFN-I and RIP3 signaling in S. Typhimurium–infected macrophages.
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影响因子：
4.6
作者：
Man SM;Karki R;Briard B;Burton A;Gingras S;Pelletier S;Kanneganti TD
通讯作者：
Kanneganti TD
影响因子：
44.1
作者：
通讯作者：
--
p62/SQSTM1形成自噬降解的蛋白质聚集体，并对亨廷顿蛋白诱导的细胞死亡具有保护作用。
影响因子：
7.8
作者：
Bjorkoy, Geir;Lamark, Trond;Brech, Andreas;Outzen, Heidi;Perander, Maria;Overvatn, Aud;Stenmark, Harald;Johansen, Terje
通讯作者：
Johansen, Terje
DOI：
10.1083/jcb.201009067
发表时间：
2011-01-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Itakura E;Mizushima N
通讯作者：
Mizushima N
影响因子：
21.3
作者：
Komatsu, Masaaki;Kurokawa, Hirofumi;Yamamoto, Masayuki
通讯作者：
Yamamoto, Masayuki