A family of conserved bacterial virulence factors dampens interferon responses by blocking calcium signaling.
A family of conserved bacterial virulence factors dampens interferon responses by blocking calcium signaling.
复制标题
DOI：
10.1016/j.cell.2022.04.028
复制
发表时间：
2022-06-23
期刊：
影响因子：
64.5
通讯作者：
Odendall, Charlotte
中科院分区：
文献类型：
--
作者：
Alphonse, Noemie;Wanford, Joseph J.;Voak, Andrew A.;Gay, Jack;Venkhaya, Shayla;Burroughs, Owen;Mathew, Sanjana;Lee, Truelian;Evans, Sasha L.;Zhao, Weiting;Frowde, Kyle;Alrehaili, Abrar;Dickenson, Ruth E.;Munk, Mads;Panina, Svetlana;Mahmood, Ishraque F.;Llorian, Miriam;Stanifer, Megan L.;Boulant, Steeve;Berchtold, Martin W.;Bergeron, Julien R. C.;Wack, Andreas;Lesser, Cammie F.;Odendall, Charlotte
干扰素 (IFN) 会诱导抗菌状态，保护组织免受感染。许多病毒抑制 IFN 信号传导，但细菌病原体是否逃避 IFN 反应仍不清楚。在这里，我们证明了志贺氏菌 OspC 家族的 III 型分泌效应子能够独立地阻断 IFN 信号传导，而与其细胞死亡抑制活性无关。相反，IFN 抑制是通过 OspC1 和 OspC3 与 Ca2+ 传感器钙调蛋白 (CaM) 的结合介导的，从而阻断 CaM 激酶 II 和下游 JAK/STAT 信号传导。缺乏 OspC1 和 OspC3 的志贺氏菌在上皮细胞和小鼠感染模型中的生长减弱。通过消除干扰素受体，这两种模型中的这种表型都得到了挽救。其他病原体中保守的 OspC 同源物不仅结合 CaM，还抑制 IFN，表明存在广泛的毒力策略。这些发现揭示了 IFN 抑制的保守但先前未描述的分子机制，并证明了 Ca2+ 和 IFN 靶向在细菌发病机制中的关键作用。干扰素 (IFN) 和 IFN 刺激基因 (ISG) 限制志贺氏菌感染 志贺氏菌 OspC1 和 OspC3 效应子阻断 IFN 信号传导和 ISG 表达 OspC 效应子结合钙调蛋白 (CaM)，抑制 CaMKII 和 STAT1 磷酸化 ΔospC1/C3 志贺氏菌在 WT 中减弱，但在 IFN 缺陷细胞和小鼠中不减弱 OspC 志贺氏菌中的 III 型分泌效应子结合钙调蛋白并阻断干扰素信号传导，与该蛋白家族的细胞死亡抑制活性无关。其他细菌物种同源物中这一功能的保守性表明 Ca2+ 和干扰素靶向在细菌发病机制中具有共同作用。
Interferons (IFNs) induce an antimicrobial state, protecting tissues from infection. Many viruses inhibit IFN signaling, but whether bacterial pathogens evade IFN responses remains unclear. Here, we demonstrate that the Shigella OspC family of type-III-secreted effectors blocks IFN signaling independently of its cell death inhibitory activity. Rather, IFN inhibition was mediated by the binding of OspC1 and OspC3 to the Ca2+ sensor calmodulin (CaM), blocking CaM kinase II and downstream JAK/STAT signaling. The growth of Shigella lacking OspC1 and OspC3 was attenuated in epithelial cells and in a murine model of infection. This phenotype was rescued in both models by the depletion of IFN receptors. OspC homologs conserved in additional pathogens not only bound CaM but also inhibited IFN, suggesting a widespread virulence strategy. These findings reveal a conserved but previously undescribed molecular mechanism of IFN inhibition and demonstrate the critical role of Ca2+ and IFN targeting in bacterial pathogenesis. Interferons (IFNs) and IFN-stimulated genes (ISGs) restrict Shigella infection Shigella OspC1 and OspC3 effectors block IFN signaling and ISG expression OspC effectors bind calmodulin (CaM), inhibiting CaMKII and STAT1 phosphorylation ΔospC1/C3 Shigella is attenuated in WT but not in IFN-deficient cells and mice The OspC type-III-secreted effectors in Shigella bind calmodulin and block interferon signaling, independently of the cell-death-inhibitory activities of this family of proteins. Conservation of this function in homologs of other bacterial species suggests a common role for Ca2+ and interferon targeting in bacterial pathogenesis.
登录
查看更多内容
DOI：
10.1126/science.abf8113
发表时间：
2021-07-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gaudet RG;Zhu S;Halder A;Kim BH;Bradfield CJ;Huang S;Xu D;Mamiñska A;Nguyen TN;Lazarou M;Karatekin E;Gupta K;MacMicking JD
通讯作者：
MacMicking JD
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
2.3
作者：
Wang M;Sun H;Zhang W;Zhang Y
通讯作者：
Zhang Y
影响因子：
14.9
作者：
Buchan, Daniel W. A.;Jones, David T.
通讯作者：
Jones, David T.
影响因子：
6.7
作者：
Caboni M;Pédron T;Rossi O;Goulding D;Pickard D;Citiulo F;MacLennan CA;Dougan G;Thomson NR;Saul A;Sansonetti PJ;Gerke C
通讯作者：
Gerke C