3.A.24.5.1
Esx-4 secretion system.  Gray et al. 2016 showed that ESX-4 is essential for conjugal recipient activity in Mycobacterium smegmatis. Transcription of esx4 genes in the recipient requires coculture with a donor strain and a functional ESX-1 apparatus in the recipient. Conversely, mutation of the donor ESX-1 apparatus amplifies the esx4 transcriptional response in the recipient. The effect of ESX-1 on esx4 transcription correlates with conjugal DNA transfer efficiencies. Thus, intercellular communication via ESX-1 controls the expression of its evolutionary progenitor, ESX-4, to promote conjugation between mycobacteria. The eight proteins listed under this TC# are all encoded withing a single gene cluster (Gray et al. 2016).  ESX-4 influences the secretion of the culture filtrate proteins Rv0125 and Rv1085c, which are also necessary for efficient heme utilization. Sankey et al. 2023 discovered that deletion of the alternative sigma factor SigM reduced M. tuberculosis (Mtb)heme utilization through two pathways and predicted that SigM is a global positive regulator of core heme utilization genes of both pathways. They presented direct evidence that some mycobacterial PPE (proline-proline-glutamate motif) proteins of the PPE protein family are pore-forming membrane proteins. They identified core components of both Mtb Heme utilization pathways and identified a novel channel-forming membrane protein of Mtb. The largest source of iron for Mtb in the human host is heme. The ancestral ESX-4 type VII secretion system is required for the efficient utilization of heme as a source of iron. This is another biological function identified for ESX-4 in Mtb. A most exciting finding is that some mycobacterial PPE (proline-proline-glutamate motif) proteins that have been implicated in the nutrient acquisition are membrane proteins that can form channels in a lipid bilayer (Sankey et al. 2023).