Non-canonical activation of the ER stress sensor ATF6 by Legionella pneumophila effectors.
Non-canonical activation of the ER stress sensor ATF6 by Legionella pneumophila effectors.
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DOI：
10.26508/lsa.202101247
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发表时间：
2021-12
影响因子：
4.4
通讯作者：
Mukherjee S
中科院分区：
文献类型：
--
作者：
Ibe NU;Subramanian A;Mukherjee S
嗜肺军团菌将毒素分泌到宿主细胞内，通过与未折叠蛋白积聚激活的典型途径不同的机制，诱导内质网应激传感器和转录因子ATF6的非规范处理和激活。胞内致病菌嗜肺军团菌(Legionella Paopphila(L.P.)将∼330效应器蛋白分泌到宿主细胞中，以塑造内质网衍生的复制生态位。我们之前报道了5例L.P.抑制IRE1的效应器，IRE1是动态平衡未折叠蛋白反应(UPR)途径的关键传感器。在本研究中，我们发现了L.P.选择性激活UPR传感器ATF6的毒素，导致其切割、核转位和靶基因转录。与传统模型不同的是，这种依赖L.P.的ATF6激活不需要将其运输到高尔基体，也不需要被S1P/S2P蛋白酶切割。我们认为，我们的发现突显了L.P.作用于三个UPR传感器，并扩大选择性扰乱宿主体内平衡途径的细菌蛋白的谱系。
Legionella pneumophila secretes toxins into the host cell that induce the non-canonical processing and activation of the ER stress sensor and transcription factor ATF6 via a mechanism that is distinct from the canonical pathway activated by unfolded protein buildup. The intracellular bacterial pathogen Legionella pneumophila (L.p.) secretes ∼330 effector proteins into the host cell to sculpt an ER-derived replicative niche. We previously reported five L.p. effectors that inhibit IRE1, a key sensor of the homeostatic unfolded protein response (UPR) pathway. In this study, we discovered a subset of L.p. toxins that selectively activate the UPR sensor ATF6, resulting in its cleavage, nuclear translocation, and target gene transcription. In a deviation from the conventional model, this L.p.–dependent activation of ATF6 does not require its transport to the Golgi or its cleavage by the S1P/S2P proteases. We believe that our findings highlight the unique regulatory control that L.p. exerts upon the three UPR sensors and expand the repertoire of bacterial proteins that selectively perturb host homeostatic pathways.
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