DOCK2 regulates antifungal immunity by regulating RAC GTPase activity.
DOCK2 regulates antifungal immunity by regulating RAC GTPase activity.
复制标题
DOCK2通过调节RAC GTPase活性来调节抗真菌免疫
DOI：
10.1038/s41423-021-00835-0
复制
发表时间：
2022-05
影响因子：
24.1
通讯作者：
Wang C
中科院分区：
文献类型：
--
作者：
Ma X;Tan X;Yu B;Sun W;Wang H;Hu H;Du Y;He R;Gao R;Peng Q;Cui Z;Pan T;Feng X;Wang J;Xu C;Zhu B;Liu W;Wang C
真菌感染每年在全世界造成约150万人死亡，目前播散性念珠菌病的死亡率超过乳腺癌和疟疾。念珠菌病高死亡率的主要原因是抗真菌药物数量有限和耐药菌种的出现。因此，更好地了解抗真菌宿主防御机制对于制定有效的预防和治疗策略至关重要。在这里，我们报告，DOCK 2（细胞质分裂奉献者2）促进不可或缺的抗真菌先天免疫信号和促炎基因表达的巨噬细胞。DOCK 2缺陷型巨噬细胞表现出减少的RAC GT3（Rac家族小GT3）活化和ROS（活性氧）产生，这反过来减弱了细胞内真菌的杀伤和下游信号传导途径的活化。在机制上，真菌刺激后，活化的SYK（脾相关酪氨酸激酶）在酪氨酸985和1405处磷酸化DOCK 2，这促进RAC GTP酶的募集和活化，然后增加ROS产生和下游信号传导活化。重要的是，纳米颗粒介导的体外转录（IVT）Rac 1 mRNA的递送可促进Rac 1的活性，并有助于消除体内真菌感染。综上所述，本研究不仅确定了DOCK 2通过调节RAC GT3活性在抗真菌免疫中的关键作用，而且还提供了通过使用IVT mRNA治疗侵袭性真菌感染的概念证据。
Fungal infections cause ~1.5 million deaths each year worldwide, and the mortality rate of disseminated candidiasis currently exceeds that of breast cancer and malaria. The major reasons for the high mortality of candidiasis are the limited number of antifungal drugs and the emergence of drug-resistant species. Therefore, a better understanding of antifungal host defense mechanisms is crucial for the development of effective preventive and therapeutic strategies. Here, we report that DOCK2 (dedicator of cytokinesis 2) promotes indispensable antifungal innate immune signaling and proinflammatory gene expression in macrophages. DOCK2-deficient macrophages exhibit decreased RAC GTPase (Rac family small GTPase) activation and ROS (reactive oxygen species) production, which in turn attenuates the killing of intracellular fungi and the activation of downstream signaling pathways. Mechanistically, after fungal stimulation, activated SYK (spleen-associated tyrosine kinase) phosphorylates DOCK2 at tyrosine 985 and 1405, which promotes the recruitment and activation of RAC GTPases and then increases ROS production and downstream signaling activation. Importantly, nanoparticle-mediated delivery of in vitro transcribed (IVT)Rac1mRNA promotes the activity of Rac1 and helps to eliminate fungal infection in vivo. Taken together, this study not only identifies a critical role of DOCK2 in antifungal immunity via regulation of RAC GTPase activity but also provides proof of concept for the treatment of invasive fungal infections by using IVT mRNA.
登录
查看更多内容
早发作感染患者的遗传DOCK2缺乏。
DOI：
10.1056/nejmoa1413462
发表时间：
2015-06-18
期刊：
The New England journal of medicine
影响因子：
--
作者：
Dobbs K;Domínguez Conde C;Zhang SY;Parolini S;Audry M;Chou J;Haapaniemi E;Keles S;Bilic I;Okada S;Massaad MJ;Rounioja S;Alwahadneh AM;Serwas NK;Capuder K;Çiftçi E;Felgentreff K;Ohsumi TK;Pedergnana V;Boisson B;Haskoloğlu Ş;Ensari A;Schuster M;Moretta A;Itan Y;Patrizi O;Rozenberg F;Lebon P;Saarela J;Knip M;Petrovski S;Goldstein DB;Parrott RE;Savas B;Schambach A;Tabellini G;Bock C;Chatila TA;Comeau AM;Geha RS;Abel L;Buckley RH;İkincioğulları A;Al-Herz W;Helminen M;Doğu F;Casanova JL;Boztuğ K;Notarangelo LD
通讯作者：
Notarangelo LD
DOI：
10.1086/523110
发表时间：
2007-11-15
期刊：
The Journal of infectious diseases
影响因子：
--
作者：
Gow NA;Netea MG;Munro CA;Ferwerda G;Bates S;Mora-Montes HM;Walker L;Jansen T;Jacobs L;Tsoni V;Brown GD;Odds FC;Van der Meer JW;Brown AJ;Kullberg BJ
通讯作者：
Kullberg BJ
DOI：
10.1084/jem.20091776
发表时间：
2010-04-12
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Gotoh K;Tanaka Y;Nishikimi A;Nakamura R;Yamada H;Maeda N;Ishikawa T;Hoshino K;Uruno T;Cao Q;Higashi S;Kawaguchi Y;Enjoji M;Takayanagi R;Kaisho T;Yoshikai Y;Fukui Y
通讯作者：
Fukui Y
DOI：
10.1083/jcb.201102095
发表时间：
2011-07-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Finkel T
通讯作者：
Finkel T
念珠菌感染和生物膜形成：超越表面。
影响因子：
5.2
作者：
Horton MV;Nett JE
通讯作者：
Nett JE