Teleological cooption of Mycobacterium tuberculosis PE/PPE proteins as porins: Role in molecular immigration and emigration

• Published in: International journal of medical microbiology Vol. 311; no. 3; p. 151495
• Main Authors: Ehtram, Aquib, Shariq, Mohd, Ali, Sabeeha, Quadir, Neha, Sheikh, Javaid A., Ahmad, Faraz, Sharma, Tarina, Ehtesham, Nasreen Z., Hasnain, Seyed E.
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.04.2021; Elsevier
• Subjects: Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Biological Transport; Cell envelop; Drug resistance; Emigration and Immigration; Molecular transport; Mycobacterium tuberculosis - metabolism; Nutrient uptake; Pathogenic bacteria; PE/PPE; Porin; Porins - genetics; Porin; Molecular transport; Cell envelop; Drug resistance; Nutrient uptake; Pathogenic bacteria; PE/PPE
• ISSN: 1438-4221; 1618-0607
• DOI: 10.1016/j.ijmm.2021.151495

Summarised depiction of the localization, secretion, and transport functions of PE/PPE proteins in M. tb. PE/PPE proteins are translocated across the mycobacterial membrane by the ESX-5 secretion system, which mediates the secretion and membrane localization of the proteins. The figure highlights the mechanistic contribution of PE/PPE proteins in the molecular import and export system of M. tb. The molecular transport functions are carried out by the PE/PPE heterodimers as well as the individual PPE protein. [Display omitted] Permeation through bacterial cells for exchange or uptake of biomolecules and ions invariably depend upon the existence of pore-forming proteins (porins) in their outer membrane. Mycobacterium tuberculosis (M. tb) harbours one of the most rigid cell envelopes across bacterial genera and is devoid of the classical porins for solute transport across the cell membrane. Though canonical porins are incompatible with the evolution of permeability barrier, porin like activity has been reported from membrane preparations of pathogenic mycobacteria. This suggests a sophisticated transport mechanism that has been elusive until now, along with the protein family responsible for it. Recent evidence suggests that these slow-growing mycobacteria have co-opted some of PE/PPE family proteins as molecular transport channels, in place of porins, to facilitate uptake of nutrients required to thrive in the restrictive host environment. These reports advocate that PE/PPE proteins, due to their structural ability, have a potential role in importing small molecules to the cell's interior. This mechanism unveils how a successful pathogen overcomes its restrictive membrane's transport limitations for selective uptake of nutrients. If extrapolated to have a role in drug transport, these channels could help understand the emergence of drug resistance. Further, as these proteins are associated with the export of virulence factors, they can be exploited as novel drug targets. There remains, however, an interesting question that as the PE/PPE proteins can allow the 'import' of molecules from outside the cell, is the reverse transport also possible across the M. tb membrane. In this review, we have discussed recent evidence supporting PE/PPE's role as a specific transport channel for selective uptake of small molecule nutrients and, as possible molecular export machinery of M. tb. This newly discovered role as transmembrane channels demands further research on this enigmatic family of proteins to comprehend the pathomechanism of this very smart pathogen.