Mycobacterium tuberculosis PE_PGRS1 promotes mycobacteria intracellular survival via reducing the concentration of intracellular free Ca2+ and suppressing endoplasmic reticulum stress

Abstract

Mycobacterium tuberculosis (M. tuberculosis) is the causative agent of tuberculosis (TB). And the PE_PGRS family members of M. tuberculosis are closely associated with virulence and antigen presentation but with function largely elusive. PE_PGRS1(Rv0109) contained 7 Ca²⁺ binding domains of GGXGXD/NXUX (X is any amino acid), which can reduce intracellular Ca²⁺ surge. In addition, PE_PGRS1 can mitigate the activation of PERK branch in endoplasmic reticulum (ER) stress by down-regulating the expression of CHOP, Bip, p-PERK, p-eIF2α, and ATF4. Interestingly, we found that two splicing variations of Bax/Bcl-2, Baxβ, and Bcl-2α, were differentially expressed after infection with Ms_PE_PGRS1, and may be involved in the regulation of apoptosis. Hence, this study identified that PE_PGRS1 is a novel calcium-associated protein that can decrease intracellular Ca²⁺ levels and the PERK axis. And the weakening of the PERK-eIF2α-ATF4 axis reduces THP-1 macrophages apoptosis, promotes the survival of mycobacteria in macrophages.

Keywords: Bax/Bcl-2 splice variation; Calcium-associated protein; ER stress; Mycobacterium tuberculosis; PERK axis.