Ubiquitin systems mark pathogen-containing vacuoles as targets for host defense by guanylate binding proteins
Ubiquitin systems mark pathogen-containing vacuoles as targets for host defense by guanylate binding proteins
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DOI：
10.1073/pnas.1515966112
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发表时间：
2015-10-13
影响因子：
11.1
通讯作者：
Coers, Joern
中科院分区：
文献类型：
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作者：
Haldar, Arun K.;Foltz, Clemence;Coers, Joern
许多微生物产生并维持含有病原体的空泡（PV）作为允许微生物生长和存活的细胞内生态位。IFN γ诱导的鸟苷酸结合蛋白（GBP）和免疫相关的GT3（IRG）宿主蛋白对PV的破坏是针对许多PV驻留病原体的成功免疫应答的关键。然而，IRG和GBP合作检测和破坏PV的机制尚不清楚。我们发现，宿主细胞与IFN γ引发提示IRG依赖性协会弓形虫和衣原体含有空泡与泛素通过调节易位的E3泛素连接酶肿瘤坏死因子（TNF）受体相关因子6（TRAF6）。这种最初的泛素标记使p62介导的GBP护送和沉积到PV，从而赋予细胞自主免疫。刚地弓形虫的高毒力菌株通过抑制IRG功能的特定棒状蛋白激酶来逃避这一过程，导致下游PV遍在化和GBP递送的阻断。我们的研究结果定义了一个以泛素为中心的机制，宿主细胞通过该机制将GBP传递给PV，并解释了高毒力寄生虫如何逃避GBP介导的免疫。
Many microbes create and maintain pathogen-containing vacuoles (PVs) as an intracellular niche permissive for microbial growth and survival. The destruction of PVs by IFN gamma-inducible guanylate binding protein (GBP) and immunity-related GTPase (IRG) host proteins is central to a successful immune response directed against numerous PV-resident pathogens. However, the mechanism by which IRGs and GBPs cooperatively detect and destroy PVs is unclear. We find that host cell priming with IFN gamma prompts IRG-dependent association of Toxoplasmaand Chlamydia-containing vacuoles with ubiquitin through regulated translocation of the E3 ubiquitin ligase tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6). This initial ubiquitin labeling elicits p62-mediated escort and deposition of GBPs to PVs, thereby conferring cell-autonomous immunity. Hypervirulent strains of Toxoplasma gondii evade this process via specific rhoptry protein kinases that inhibit IRG function, resulting in blockage of downstream PV ubiquitination and GBP delivery. Our results define a ubiquitin-centered mechanism by which host cells deliver GBPs to PVs and explain how hypervirulent parasites evade GBP-mediated immunity.