Role of TlyA in the Biology of Uncultivable Mycobacteria

TlyA proteins are related to distinct functions in a diverse spectrum of bacterial pathogens, including mycobacterial spp. There are several annotated proteins that function as hemolysin or pore-forming molecules that play an important role in the virulence of pathogenic organisms. Many studies reported the dual activity of mycobacterial TlyA as ‘hemolysin’ and ‘Sadenosylmethionine dependent rRNA methylase’. To act as a hemolysin, a sequence must have a signal sequence and transmembrane segment, which helps the protein enter the extracellular environment. Interestingly, the mycobacterial tlyA has neither traditional signal sequences of general/ sec/tat pathways nor any transmembrane segments. Still, it can reach the extracellular milieu with the help of non-classical signal mechanisms. Also, retention of tlyA in cultivable mycobacterial pathogens (such as Mycobacterium tuberculosis and M. marinum) as well as uncultivated mycobacterial pathogens despite their extreme reductive evolution (such as M. leprae, M. lepromatosis and M. uberis) suggests its crucial role in the evolutionary biology of pathogenic mycobacteria. Numerous virulence factors have been characterised by the uncultivable mycobacteria, but the information of TlyA protein is still limited in terms of molecular and structural characterisation. The genomic insights offered by comparative analysis of TlyA sequences and their conserved domains reveal pore-forming activity, which further confirms its role as a virulence protein, particularly in uncultivable mycobacteria. Therefore, this review presents a comparative analysis of the mycobacterial TlyA family by sequence homology and alignment to improve our understanding of this unconventional hemolysin and RNA methyltransferase TlyA of uncultivable mycobacteria.