Ehtram Aquib, Shariq Mohd, Ali Sabeeha, Quadir Neha, Sheikh Javaid A, Ahmad Faraz, Sharma Tarina, Ehtesham Nasreen Z, Hasnain Seyed E
Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, New Delhi, India.
ICMR-National Institute of Pathology, Ansari Nagar West, New Delhi, India.
Int J Med Microbiol. 2021 Apr;311(3):151495. doi: 10.1016/j.ijmm.2021.151495. Epub 2021 Mar 9.
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.
生物分子和离子通过细菌细胞进行交换或摄取，这一过程总是依赖于其外膜中形成孔道的蛋白质（孔蛋白）的存在。结核分枝杆菌在所有细菌属中拥有最坚固的细胞壁之一，并且缺乏用于溶质跨细胞膜运输的经典孔蛋白。尽管典型的孔蛋白与通透性屏障的进化不兼容，但已报道致病性分枝杆菌的膜制剂具有类似孔蛋白的活性。这表明存在一种复杂的运输机制，直到现在这种机制还难以捉摸，同时也不清楚负责该机制的蛋白质家族。最近的证据表明，这些生长缓慢的分枝杆菌已经选择了一些PE/PPE家族蛋白作为分子运输通道，取代了孔蛋白，以促进在限制性宿主环境中生长所需营养物质的摄取。这些报道表明，PE/PPE蛋白由于其结构特性，在将小分子导入细胞内部方面具有潜在作用。这种机制揭示了一种成功的病原体如何克服其限制性膜的运输限制，以选择性摄取营养物质。如果推断其在药物运输中起作用，这些通道有助于理解耐药性的产生。此外，由于这些蛋白质与毒力因子的输出有关，它们可以被开发为新型药物靶点。然而，仍然存在一个有趣的问题，即由于PE/PPE蛋白可以允许细胞外分子的“导入”，那么结核分枝杆菌膜上的反向运输是否也可能。在这篇综述中，我们讨论了最近的证据，这些证据支持PE/PPE作为选择性摄取小分子营养物质的特定运输通道以及作为结核分枝杆菌可能的分子输出机制的作用。作为跨膜通道的这一新发现的作用需要对这个神秘的蛋白质家族进行进一步研究，以理解这种非常聪明的病原体的致病机制。
