A mycobacterial effector promotes ferroptosis-dependent pathogenicity and dissemination.
A mycobacterial effector promotes ferroptosis-dependent pathogenicity and dissemination.
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DOI：
10.1038/s41467-023-37148-x
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发表时间：
2023-03-17
影响因子：
16.6
通讯作者：
Wang, Jing
中科院分区：
文献类型：
--
作者：
Qiang, Lihua;Zhang, Yong;Lei, Zehui;Lu, Zhe;Tan, Shasha;Ge, Pupu;Chai, Qiyao;Zhao, Mengyuan;Zhang, Xinwen;Li, Bingxi;Pang, Yu;Zhang, Lingqiang;Liu, Cui Hua;Wang, Jing
铁凋亡是一种脂质过氧化驱动的铁依赖性程序性细胞死亡，涉及多种生理过程和多种疾病。新出现的证据表明，一些病原体操纵铁凋亡的致病性和传播，但潜在的分子机制仍然难以捉摸。在这里，我们确定，蛋白酪氨酸磷酸酶A（PtpA），一种由结核病（TB）引起的病原体结核分枝杆菌（Mtb）分泌的效应物，触发ferroptosis，以促进Mtb的致病性和传播。机制上，PtpA通过其Cys 11位点与宿主RanGDP相互作用进入宿主细胞核。然后，核PtpA通过靶向蛋白质精氨酸甲基转移酶6（PRMT 6）增强组蛋白H3精氨酸2（H3 R2 me 2a）的不对称二甲基化，从而抑制谷胱甘肽过氧化物酶4（GPX 4）的表达，最终诱导铁凋亡，从而促进Mtb的致病性和传播。总之，我们的研究结果提供了病原体诱导的铁凋亡的分子机制的见解，表明通过阻断Mtb PtpA-宿主PRMT 6界面靶向GPX 4依赖性铁凋亡的潜在TB治疗。铁凋亡是一种依赖铁的细胞死亡形式，其在感染性疾病中的作用正在阐明。在此，Qiang等人表明，结核分枝杆菌分泌的效应子PtpA通过劫持宿主精氨酸甲基转移酶PRMT 6来诱导铁凋亡，以促进其致病性和传播。
Ferroptosis is a lipid peroxidation-driven and iron-dependent programmed cell death involved in multiple physical processes and various diseases. Emerging evidence suggests that several pathogens manipulate ferroptosis for their pathogenicity and dissemination, but the underlying molecular mechanisms remain elusive. Here, we identify that protein tyrosine phosphatase A (PtpA), an effector secreted by tuberculosis (TB)-causing pathogen Mycobacterium tuberculosis (Mtb), triggers ferroptosis to promote Mtb pathogenicity and dissemination. Mechanistically, PtpA, through its Cys11 site, interacts with host RanGDP to enter host cell nucleus. Then, the nuclear PtpA enhances asymmetric dimethylation of histone H3 arginine 2 (H3R2me2a) via targeting protein arginine methyltransferase 6 (PRMT6), thus inhibiting glutathione peroxidase 4 (GPX4) expression, eventually inducing ferroptosis to promote Mtb pathogenicity and dissemination. Taken together, our findings provide insights into molecular mechanisms of pathogen-induced ferroptosis, indicating a potential TB treatment via blocking Mtb PtpA-host PRMT6 interface to target GPX4-dependent ferroptosis. Ferroptosis is an iron-dependent form of cell death whose role in infectious diseases is being elucidated. Here, Qiang et al. show that PtpA, an effector secreted by Mycobacterium tuberculosis, induces ferroptosis by hijacking host arginine methyltransferase PRMT6 to promote its pathogenicity and dissemination.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
3.1
作者：
Chackerian, AA;Alt, JM;Behar, SM
通讯作者：
Behar, SM
抑制蛋白质精氨酸甲基转移酶 6 可减少活性氧的产生并减弱氨基糖苷类和顺铂诱导的毛细胞死亡
影响因子：
12.4
作者：
He, Yingzi;Li, Wen;Li, Huawei
通讯作者：
Li, Huawei
影响因子：
15.9
作者：
Dar, Haider H.;Tyurina, Yulia Y.;Kagan, Valerian E.
通讯作者：
Kagan, Valerian E.
影响因子：
4.2
作者：
Mitchell, Lorna H.;Drew, Allison E.;Copeland, Robert A.
通讯作者：
Copeland, Robert A.