Did the loss of two-component systems initiate pseudogene accumulation in Mycobacterium leprae?

Jaya S. Tyagi and Deepak K. Saini

Department of Biotechnology, All India Institute of Medical Sciences, New Delhi-110029, India

Correspondence
Jaya S. Tyagi
(jstyagi{at}hotmail.com)

The predilection of the leprosy bacillus for peripheral nerves and cutaneous tissues is indicative of its restricted ability to adapt to microenvironments prevailing in other anatomical sites in the body. No pathogen, Mycobacterium leprae included, is likely to self-limit its options in terms of the tissues it targets and proliferates in. Rather, it seems some compelling circumstances would have contributed to its narrow preferences in lifestyle. In a recent report, Madan Babu (2003) suggested that the loss of sigma factors could have initiated the accumulation of pseudogenes in the M. leprae genome. It is a very interesting analysis and suggests how normal genes could turn into pseudogenes through non-random events triggered by the loss of sigma factors.

RNA polymerases utilize alternative sigma factors to enable bacteria to express discrete gene sets in response to various physiological and environmental stimuli. Mycobacterium tuberculosis has several sigma factors to choose from; its genome encodes 13 (Cole et al., 1998). The importance of sigma factors is highlighted by studies of SigE, SigH and SigF, whose loss has rendered tubercle bacilli sensitive to various environmental stresses (such as heat shock, oxidative stress and growth in macrophages) and in some cases caused an attenuated virulence phenotype (Manganelli et al., 2001, 2002; Raman et al., 2001; Chen et al., 2000; Kaushal et al., 2002). It is noteworthy that M. leprae retains only four sigma factor genes (including sigA, the primary mycobacterial sigma factor) while losing most of them, including sigF, sigH, etc. (Cole et al., 2001). sigF expression is induced under a variety of conditions, including anaerobiosis in M. tuberculosis (Michele et al., 1999; Sherman et al., 2001), and it is tempting to think that the deletion of this and/other sigma factors in M. leprae prevents its adaptation to these conditions. Furthermore, {sigma}F activity can be post-translationally modulated by anti- and anti-anti-sigma factors (Beaucher et al., 2002) in M. tuberculosis but not in M. leprae, because the latter lost the relevant genes. As a general trend, most ECF sigma factors are co-transcribed with one or more negative regulators that function as anti-sigma factors, bind to the sigma factors and inhibit their activity. In response to an environmental stimulus, the sigma factor is released and in association with the core RNA polymerase stimulates transcription. These anti-sigma/sigma pairs are analogous to the histidine sensor kinase/response regulator pairs that comprise typical two-component systems, in that both systems orchestrate an appropriate cellular response to environmental signals. Furthermore, there are many examples of signal transduction systems regulating the activity of sigma factors in response to environmental stresses (Paget et al., 1999; Klauck et al., 2001; Akbar et al., 2001; Nizan-Koren et al., 2003).

So is the loss of sigma factors all there is to the accumulation of pseudogenes in M. leprae? We propose that the loss of specific global signal transduction systems such as eukaryotic-like Ser/Thr protein kinases or two-component systems could have severely compromised M. leprae's capacity to adapt to environments that individual systems were designed to sense and respond to. The loss in this ability would over time result in the decay of genes, including sigma factor(s), participating in that specific response. To illustrate this point, let us consider the hypoxia response of mycobacteria. Both the slow- and rapid-growing species, including M. tuberculosis, Mycobacterium bovis and Mycobacterium smegmatis, adapt to conditions of oxygen limitation (Wayne & Sohaskey, 2001) by a molecular mechanism that is conserved in them and involves a two-component system, DevR–DevS (Sherman et al., 2001; Mayuri et al., 2002; Boon & Dick, 2002; O'Toole et al., 2003), which was first identified in M. tuberculosis (Dasgupta et al., 2000). DevR/DosR has recently been shown to regulate the hypoxia-responsive expression of several mycobacterial genes (Boon & Dick, 2002; O'Toole et al., 2003; Park et al., 2003). As mentioned, large-scale changes in gene expression were noted in M. tuberculosis cultures exposed briefly to hypoxia. Using the dataset that was generated by microarray RNA expression analysis (Sherman et al., 2001), we performed a simple search in the annotated M. leprae genome for orthologues to M. tuberculosis genes whose expression was substantially altered under hypoxic conditions (Table 1). The analysis revealed some interesting points. Among the top 68 protein-coding genes analysed, 46 were either pseudogenes or absent from M. leprae (Cole et al., 2001) and included those encoding the DevR–DevS two-component system. This translates to a loss of ~68 % of the genes analysed and equals in magnitude to a 69 % loss of sigma factor genes. Furthermore, genes conserved in M. leprae included those encoding proteins that are likely to have functions in addition to hypoxic adaptation and included heat-shock and stress-induced proteins, transporters, proteins involved in fatty acid and polyketide biosynthesis and conserved proteins of unknown function. This pattern of loss and conservation is indicative of a selective loss of those genes that are regulated during hypoxia. On this basis, we propose that the primary loss of DevR–DevS triggered the accumulation of mutations in the genes of the hypoxia regulon in M. leprae. Apart from DevR–DevS, M. leprae has also lost six of 11 orthologues each of M. tuberculosis two-component systems, orphan two-component systems and Ser/Thr protein kinases (Cole et al., 2001), the decay of which could have triggered the accumulation of pseudogenes in their respective regulons.


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Table 1. M. leprae orthologues to hypoxia-responsive genes of M. tuberculosis

Genes that displayed >=3·0-fold change in signal from baseline during microarray hybridization analysis (Sherman et al., 2001) were taken for this analysis.

 
Regardless of whether the deletion of two-component systems preceded that of sigma factor genes or vice versa, the question still remains as to why so many systems regulating adaptive processes were susceptible to gene decay in M. leprae. Perhaps by setting in motion the process of decay of regulatory genes and as a consequence of natural selection wherein the retention of useful traits was the key, the emergence of pseudogenes among structural genes under the control of various mutated environmentally responsive regulatory genes was inevitable over time. As a corollary, only those genes were retained that participated in processes absolutely essential to the leprosy bacillus.

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