Bacterial secretion chaperones: the mycobacterial type VII case

Abstract

Chaperones are central players in maintaining the proteostasis in all living cells. Besides highly conserved generic chaperones that assist protein folding and assembly in the cytosol, additional more specific chaperones have evolved to ensure the successful trafficking of proteins with extra-cytoplasmic locations. Associated with the distinctive secretion systems present in bacteria, different dedicated chaperones have been described that not only keep secretory proteins in a translocation competent state, but often are also involved in substrate targeting to the specific translocation channel. Recently, a new class of such chaperones has been identified that are involved in the specific recognition of substrates transported via the type VII secretion pathway in mycobacteria. In this minireview, we provide an overview of the different bacterial chaperones with a focus on their roles in protein secretion and will discuss in detail the roles of mycobacterial type VII secretion chaperones in substrate recognition and targeting.

New insights into the mycobacterial PE and PPE proteins provide a framework for future research

“…This PE and PPE complex structure highly resembles the structure of the heterodimers formed by Esx proteins, such as EsxA‐EsxB (ESAT‐6/CFP10) (Renshaw et al , ; Poulsen et al , ), or even the Staphylococcus aureus EsxA or EsxC homodimers (Sundaramoorthy et al , ; Anderson et al , ; Ates et al , ). The structure of PE and PPE proteins is also highly reminiscent of that of a number of ESX‐1 secretion‐associated proteins (esp) proteins such as the EspA/C and EspE/F heterodimers and EspB (Bitter et al , ; Solomonson et al , ; Lou et al , ; Phan et al , ; Phan and Houben, ). Together, these data suggest that the helix‐bundle structure and composite secretion signal are among the defining features of PE and PPE heterodimers and other TypeVII‐associated substrates (Daleke et al , ).…”

“…Instead, they bind to cytosolic EspG chaperones and thereby confer system specificity to these substrates (Fig. ; Daleke et al , ; Ekiert and Cox, ; Korotkova et al , ; Phan et al , ; Phan and Houben, ). Intriguingly, exchanging the EspG interacting domain of the ESX‐1 secreted PPE68_1 with that of the ESX‐5 substrate PPE18 was sufficient to reroute this protein from ESX‐1 to ESX‐5 in M. marinum (Phan et al , ).…”

“…Intriguingly, exchanging the EspG interacting domain of the ESX‐1 secreted PPE68_1 with that of the ESX‐5 substrate PPE18 was sufficient to reroute this protein from ESX‐1 to ESX‐5 in M. marinum (Phan et al , ). Therefore, the sequence of the EspG‐binding domain of the PPE protein may be sufficient to predict system specificity of PPE proteins, although experimental validation of this hypothesis remains incomplete beyond the ESX‐1 and ESX‐5 systems (Ekiert and Cox, ; Korotkova et al , ; Chen et al , ; Phan and Houben, ). Many of these studies have been performed in the model organism M. marinum , but most results have been verified in M. tuberculosis .…”

“…These operonic clusters are likely to be the first pe and ppe genes duplicated from the esx genetic loci after introduction of the ESX‐5 system into the most‐recent common ancestor of the slow‐growing mycobacteria (Gey van Pittius et al , ; Fishbein et al , ; Dumas et al , ). The PE and PPE proteins encoded by such operons are thought to be exclusively secreted as PE and PPE heterodimers that may not be promiscuous to other secretion partners (Ekiert and Cox, ; Korotkova et al , ; Chen et al , ; Phan et al , ; Phan and Houben, ). A notable example of such operonic organization is the PE8‐PPE15‐EsxI‐EsxJ operon, which was shown to facilitate protein secretion of other TypeVII and non‐TypeVII substrates (Shah et al , ).…”

“…A conserved WxG motif is found between the second and third alpha helix of all PPE proteins, but PPE proteins do not contain the YxxxD/E secretion signal ( Fig. 1; Daleke et al, 2012a;Phan and Houben, 2018).…”