The role of Ser/Thr/Tyr phosphosignaling in the M. tuberculosis latency switch

 描述(申请人提供)：结核分枝杆菌(Mtb)的一个决定性特征是它能够表现为一种可持续多年的潜伏感染。潜伏性结核病影响着近20亿人，在世界大部分地区，重新激活结核分枝杆菌是导致绝大多数活动性结核病(TB)的原因。在这种情况下，潜伏期和重新激活决定了结核分枝杆菌的发病和传播，并成为结核病控制的主要障碍。细菌的信号机制和效应器驱动潜伏期和再激活之间的开关(潜伏期开关)几乎完全未知。支持其他细菌这种类型转变的信号转导是通过磷酸化途径传播的。使用一个高度重复性的，定义的体外低氧和复氧模型来模拟Mtb的潜伏期和重新激活，我们现在证明了Ser/Thr蛋白激酶PknB及其同源磷酸酶PSTP是对氧气反应的复制的主要调节因子，并表明PknB受到一种新的Mtb翻译后修饰蛋白Tyr磷酸化的调节。基于这些数据，我们假设Ser/Thr和Tyr磷酸信号控制着Mtb的潜伏期开关。通过定义一个控制Mtb对氧分压变化的生理反应的磷信号系统-PKnB和PSTP，我们提供了一个机会来确定执行低氧适应的相关下游底物和效应器。这些发现将揭示控制潜伏期和重新激活的信号通路和效应器。

 DESCRIPTION (provided by applicant): A defining feature of Mycobacterium tuberculosis (Mtb) is its ability to manifest as a latent infection that can last for many years. Latent tuberculosis affects nearly 2 billion people, and in much of the world, reactivating Mtb is responsible for the vast majority of active tuberculosis (TB). In this way, latency and reactivatio shape Mtb pathogenesis and transmission and are major impediments to TB control. The bacterial signaling mechanisms and effectors driving the switch between latency and reactivation (the latency switch) are almost entirely unknown. The signal transduction that underpins transitions of this type in other bacteria propagates through phosphorylation pathways. Using a highly reproducible, defined in vitro model of hypoxia followed by reaeration to model latency and reactivation in Mtb, we now show that the Ser/Thr protein kinase PknB and its cognate phosphatase, PstP, are major regulators of replication in response to oxygen and show that PknB is regulated by a new Mtb posttranslational modification, protein Tyr phosphorylation. Based on these data, we hypothesize that Ser/Thr and Tyr phosphosignaling control the Mtb latency switch. By defining a phosphosignaling system- PknB and PstP- that controls the physiologic response of Mtb to shifting oxygen tension, we provide an opportunity to identify the relevant downstream substrates and effectors that execute hypoxia adaptations. These findings will uncover signaling pathways and effectors that control latency and reactivation.