细菌VI型分泌系统抗环境胁迫新功能研究及其作用机制解析

The newly discovered bacterial type VI secretion systems are widely distributed in a broad spectrum of bacteria, and involved in a broad diversity of physiological processes. In this study we aim to dissect the mechanism of T6SS in environmental stress resistance, a novel function of T6SS that has not been well investigated. Our original results have led to a model in which an OxyR activated T6SS in Yersinia pseudotuberculosis (T6SS-4) imports Mn2+ and Zn2+ as antioxidants via competitively inhibition of the Fenton reaction upon sensing oxidative stress signals, thereby inhibiting the production of free radicals, in order to improve bacterial tolerance to oxidative stress. After completion of this model, we will further reveal the molecular mechanism of T6SS in osmotic stress resistance and cross-protection based on our new findings that T6SS-4 functions in reducing intracellular free radical levels and is resistant to a variety of environmental stresses. Through the implementation of this project, we will not only answer some of the key scientific issues in the field of T6SS resistance to environmental stress, but also reveal the ion transport function of T6SS that may lead to a major breakthrough for the whole T6SS research.

新型细菌分泌系统T6SS是当前微生物领域一个新的研究热点。本项目在我们近期取得的关于假结核耶尔森氏菌T6SS-4抗环境胁迫生理功能及其作用机制等研究结果基础上，初步提出一个假结核耶尔森氏菌T6SS-4抗氧胁迫机制的模型，即在氧胁迫下由OxyR感受活性氧信号并上调T6SS-4表达，T6SS-4通过泵入Mn2+和Zn2+而竞争抑制芬顿反应，从而抑制自由基的产生，以提高细菌对氧胁迫的耐受能力。本项目首先将验证并逐步完善此模型，其次将利用T6SS-4具有多种抗环境胁迫功能的特性，及其降低胞内自由基水平这一新发现，解析其抗渗透压胁迫的分子机制，并初步揭示不同逆境胁迫的交叉保护机制这一重要科学问题。通过本项目的实施，不仅将回答当前T6SS抗环境胁迫领域存在的一些关键科学问题，从而将T6SS抗环境胁迫领域的研究不断推向深入，并有可能揭示T6SS的离子转运新功能，为T6SS领域研究带来重要突破。

新型细菌分泌系统T6SS是当前微生物领域一个新的研究热点。在本项目中，我们首次鉴定到一个具有Zn2+结合功能的效应蛋白YezP，其具有协助T6SS系统在胁迫环境下向胞内转运锌离子以抑制芬顿反应，降低胞内羟基自由基水平以对抗初级和次级氧胁迫的功能，初步揭示了不同逆境胁迫的交叉保护机制；进一步还发现了T6SS分泌的锌离子结合型效应蛋白通过与外膜血红素转运蛋白HmuR协同转运锌离子抗氧胁迫的途径；接着我们还发现T6SS可以分泌锰离子结合蛋白转运锰离子并抗氧化胁迫，并揭示了其转运机制；此外还发现T6SS可通过与PQS相互作用招募细菌外膜囊泡转运铁抗胁迫的机制和途径。该系列发现在国际上率先揭示了一类离子转运型T6SS效应蛋白的存在，研究结果相继在Nature子刊、Cell子刊和PNAS等国际顶尖期刊发表，并获得Faculty of 1000推荐，开创了T6SS离子转运和抗环境胁迫研究新方向。