Mycobacterium tuberculosis EspK Has Active but Distinct Roles in the Secretion of EsxA and EspB

Abstract

Mycobacterium tuberculosis uses its ESX-1 system to secrete EsxA and EspB into a host to cause disease. We show that EspK, a protein whose role in the ESX-1 machinery was thought to be nonessential, is needed by M. tuberculosis for optimal EsxA and EspB secretion.

Proteo-genetic analysis reveals clear hierarchy of ESX-1 secretion in Mycobacterium marinum

“…The processed form of EspB, which corresponds to its N-terminal half, forms heptameric rings ( 33 ). EspK functions to keep EspB from oligomerizing inside of the mycobacterial cell ( 71 ).…”

The crystal structure of the EspB-EspK virulence factor-chaperone complex suggests an additional type VII secretion mechanism in Mycobacterium tuberculosis

“…However, since then, multiple studies have shown the presence of EspK in the capsule or culture filtrate ( 38 , 54 , 55 ). Recently ( 39 ), it was shown that EspK is exported by M. tuberculosis to be localized in its cell wall. As EspB oligomerizes upon secretion, it is expected that any control on this event would happen before its secretion.…”

“…As EspB oligomerizes upon secretion, it is expected that any control on this event would happen before its secretion. We hypothesize that EspK binds to EspB to prevent a premature oligomerization that could stop its secretion ( 39 ). We have shown that one of the factors that favors EspB oligomerization is cleavage of its C-terminal region, which occurs during secretion within the periplasm, as well as the presence of an acidic environment ( 29 ).…”

“…Lim et al . ( 39 ) write that a direct physical interaction between M. tuberculosis EspB and EspK requires the WxG motif of EspK, which is located in its N-terminus. Others suggested that only the EspK C-terminal domain interacts with the EspB N-terminus in the cytosol, which is then delivered to EccCb 1 for secretion ( 32 ).…”

Phase variation as a major mechanism of adaptation inMycobacterium tuberculosiscomplex

“…Multiple different pressures may differentially select for variants related to ESX-1 activity. This secretion system influences virulence and antigenicity in MTBC (Garces et al, 2010; Lim et al, 2022) by controlling the secretion of the immunodominant antigens ESAT-6 ( esxA ) and CFP-10 ( esxB ) (Covert et al, 2001; Guinn et al, 2004; Hsu et al, 2003), stimulating the innate immune response and cytokine secretion (Pandey et al, 2009, p. 2; Stanley et al, 2007), and promoting the intracellular growth of the pathogen (Lewis et al, 2003; Stanley et al, 2003). Through modulating the immune response, as well as cellular permeability (Garces et al, 2010), ESX-1 function may also influence antibiotic activity or resistance (Torres Ortiz et al, 2021).…”