Abstract
The principal virulence determinant of Mycobacterium tuberculosis (Mtb), the ESX-1 protein secretion system, is positively controlled at the transcriptional level by EspR. Depletion of EspR reportedly affects a small number of genes, both positively or negatively, including a key ESX-1 component, the espACD operon. EspR is also thought to be an ESX-1 substrate. Using EspR-specific antibodies in ChIP-Seq experiments (chromatin immunoprecipitation followed by ultra-high throughput DNA sequencing) we show that EspR binds to at least 165 loci on the Mtb genome. Included in the EspR regulon are genes encoding not only EspA, but also EspR itself, the ESX-2 and ESX-5 systems, a host of diverse cell wall functions, such as production of the complex lipid PDIM (phenolthiocerol dimycocerosate) and the PE/PPE cell-surface proteins. EspR binding sites are not restricted to promoter regions and can be clustered. This suggests that rather than functioning as a classical regulatory protein EspR acts globally as a nucleoid-associated protein capable of long-range interactions consistent with a recently established structural model. EspR expression was shown to be growth phase-dependent, peaking in the stationary phase. Overexpression in Mtb strain H37Rv revealed that EspR influences target gene expression both positively or negatively leading to growth arrest. At no stage was EspR secreted into the culture filtrate. Thus, rather than serving as a specific activator of a virulence locus, EspR is a novel nucleoid-associated protein, with both architectural and regulatory roles, that impacts cell wall functions and pathogenesis through multiple genes.
Highlights
Details of the genetic control mechanisms governing the pathogenicity of the etiological agent of human tuberculosis are starting to emerge [1]
It has been postulated that the DNAbinding protein EspR [2] controls the virulence of Mycobacterium tuberculosis (Mtb) by regulating expression of EspA, an exported protein [3,4], which is required for the ESX-1 system to function normally
A major infection mechanism employed by the causative agent of tuberculosis, Mycobacterium tuberculosis (Mtb), is the ESX-1 secretion system
Summary
Details of the genetic control mechanisms governing the pathogenicity of the etiological agent of human tuberculosis are starting to emerge [1]. Dimers can dimerize multimerize and recognize distal DNA binding sites in a cooperative manner as has been observed by atomic force microscopy (AFM) of EspR-nucleoprotein complexes at the espA locus, where DNA bending and bridging resulted in loop formation [10]. This behavior is characteristic of nucleoid-associated proteins (NAPs) rather than that of a classical gene activator protein [12,13]. NAPs function in a quite different manner to transcriptional activators, which typically recognize a limited number of sites in the genome and promote transcription through direct interaction with RNA polymerase
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