Regulation of the Mycobacterium tuberculosis hypoxic response gene encoding α-crystallin
Regulation of the Mycobacterium tuberculosis hypoxic response gene encoding α-crystallin
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DOI：
10.1073/pnas.121172498
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发表时间：
2001-06-19
影响因子：
11.1
通讯作者：
Schoolnik, GK
中科院分区：
文献类型：
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作者：
Sherman, DR;Voskuil, M;Schoolnik, GK
与许多对其宿主具有明显毒性的病原体不同，结核分枝杆菌的主要毒力决定因素似乎是其在临床潜伏状态下在人体内持续数年或数十年的能力。自世纪早期以来，潜伏期与宿主体内的缺氧条件有关，但M.肺结核与低氧信号的关系仍然不清楚。分枝肺结核α-晶体蛋白（acr）基因在低氧条件下可被迅速而有效地诱导，这为我们提供了一种鉴定低氧反应调节因子的方法。使用全基因组微阵列，我们确定了> 100个基因，其表达被定义的缺氧条件迅速改变。许多参与生物合成和有氧代谢的基因被抑制，而高比例的诱导基因没有已知的功能。在诱导的基因是一个明显的操纵子，包括推定的双组分反应调节对Rv 3133 c/Rv 3132 c。当我们通过靶向破坏上游基因Rv 3134 c来中断该操纵子的表达时，acr的低氧调节被消除。这些结果表明Rv 3132 c/3133 c/3134 e在分枝杆菌潜伏期中的可能作用。
Unlike many pathogens that are overtly toxic to their hosts, the primary virulence determinant of Mycobacterium tuberculosis appears to be its ability to persist for years or decades within humans in a clinically latent state. Since early in the 20th century latency has been linked to hypoxic conditions within the host, but the response of M. tuberculosis to a hypoxic signal remains poorly characterized. The M. tuberculosis alpha -crystallin (acr) gene is powerfully and rapidly induced at reduced oxygen tensions, providing us with a means to identify regulators of the hypoxic response. Using a whole genome microarray, we identified > 100 genes whose expression is rapidly altered by defined hypoxic conditions. Numerous genes involved in biosynthesis and aerobic metabolism are repressed, whereas a high proportion of the induced genes have no known function. Among the induced genes is an apparent operon that includes the putative two-component response regulator pair Rv3133c/Rv3132c. When we interrupted expression of this operon by targeted disruption of the upstream gene Rv3134c, the hypoxic regulation of acr was eliminated. These results suggest a possible role for Rv3132c/3133c/3134e in mycobacterial latency.