Host Cytosolic Glutathione Sensing by a Membrane Histidine Kinase Activates the Type VI Secretion System in an Intracellular Bacterium
Host Cytosolic Glutathione Sensing by a Membrane Histidine Kinase Activates the Type VI Secretion System in an Intracellular Bacterium
复制标题
DOI：
10.1016/j.chom.2015.06.002
复制
发表时间：
2015-07-08
影响因子：
30.3
通讯作者：
Gan, Yunn-Hwen
中科院分区：
文献类型：
--
作者：
Wong, Jocelyn;Chen, Yahua;Gan, Yunn-Hwen
VI型分泌系统（t6ss）是许多革兰氏阴性菌的主要毒力机制，但激活它们的生理信号尚不清楚。假假杆菌伯克氏菌的T6SS1在哺乳动物宿主的发病中是必不可少的，并且仅在细菌在细胞内时表达。我们发现T6SS1激活的信号存在于宿主细胞质中。通过定点诱变和生化研究，我们确定了低分子量硫醇，特别是谷胱甘肽，作为组氨酸激酶传感器病毒上的周质半胱氨酸残基（C62）的信号。谷胱甘肽暴露后，二聚体病毒通过C62还原转化为单体。当宿主中的谷胱甘肽被耗尽时，T6SS1的表达被破坏，细菌不再能够诱导多核巨细胞形成，而多核巨细胞是T6SS1功能的标志。因此，胞内细菌利用宿主胞质中丰富的谷胱甘肽作为信号，在适当的时间和地点表达毒力。
Type VI secretion systems(T6SSs) are major virulence mechanisms in many Gram-negative bacteria, but the physiological signals that activate them are not well understood. The T6SS1 of Burkholderia pseudomallei is essential for pathogenesis in mammalian hosts and is only expressed when the bacterium is intracellular. We found that signals for T6SS1 activation reside in the host cytosol. Through site-directed mutagenesis and biochemical studies, we identified low molecular weight thiols, particularly glutathione, as the signal sensed by a periplasmic cysteine residue (C62) on the histidine kinase sensor VirA. Upon glutathione exposure, dimeric VirA is converted to monomers via reduction at C62. When glutathione in the host was depleted, T6SS1 expression was abrogated, and bacteria could no longer induce multinucleate giant cell formation, the hallmark of T6SS1 function. Therefore, intracellular bacteria exploit the abundance of glutathione in host cytosol as a signal for expression of virulence at the appropriate time and place.