PE_PGRS62 promotes the survival of Mycobacterium smegmatis within macrophages via disrupting ER stress‐mediated apoptosis

Abstract

Mycobacterium tuberculosis, the leading causative agent of tuberculosis, remains one of the most deadly infectious pathogens. PE_PGRS proteins become a new focus as their species specificity in mycobacteria, especially in pathogenic mycobacteria.Despite intensive research, PE_PGRS proteins are still a mysterious aspect of mycobacterial pathogenesis with unknown mechanism. Herein, we focused on a PE_PGRS member from M. tuberculosis, PE_PGRS62, characterized by a surfaceexposed protein function in disrupting phagolysosome maturation. Expression of PE_PGRS62 in Mycobacterium smegmatis, a nonpathogenic species naturally deficient in PE_PGRS genes, resulted in enhanced resistance to various in vitro stresses and cellular survival in macrophage. As a consequence, the cytokine profiles of macrophage were disturbed and cell apoptosis were inhibited via decreasing endoplasmic reticulum stress response.

Role of the PE/PPE Family in Host–Pathogen Interactions and Prospects for Anti-Tuberculosis Vaccine and Diagnostic Tool Design

“…PE_PGRS30 and PE_PGRS47 knockout strains lost the ability to inhibit phagosome fusion ( Iantomasi et al, 2012 ; Saini et al, 2016 ). Similarly, overexpressed PE_PGRS62 significantly inhibits phagosome maturation ( Huang et al, 2012 ; Thi et al, 2013 ; Long et al, 2019 ). During phagocytosis, the transcription level of PPE25 is upregulated, and PPE25 mutant strain loses its ability to replicate within macrophages and prevent phagosome-lysosome fusion ( Jha et al, 2010 ).…”

“…Recent studies indicate that PPE32 ( Deng et al, 2016 ) and PE_PGRS5 ( Grover et al, 2018 ) are involved in ER stress-mediated cell apoptosis. Conversely, PE_PGRS62 ( Long et al, 2019 ) and PE_PGRS18 ( Yang W. et al, 2017 ) can decrease apoptosis and enhance survival rate. PE31 increased guanylate-binding protein-1 (GBP-1) expression and inhibited caspase-3 activation and macrophage apoptosis through the NF-κB pathway ( Ali et al, 2020 ).…”

PE_PGRS: Vital proteins in promoting mycobacterial survival and modulating host immunity and metabolism

“…PE_PGRS41 also inhibits the activation of caspase‐3 and caspase‐9, thus apoptosis (Deng et al, 2017). Heterogeneous expression of PE_PGRS62 in M. smegmatis inhibits endoplasmic reticulum stress response (ERS)‐mediated cell apoptosis (Huang et al, 2010; Long et al, 2019).…”

Intelligent Mechanisms of Macrophage Apoptosis Subversion by Mycobacterium

“…Mtb PE_PGRS family proteins are the most abundant cell wall anchored proteins that are implicated in bacilli adhesion, invasion, and survival within macrophages and dendritic cells [23]. PE_PGRS62, PE_PGRS41, and PE_PGRS18 contribute actively to revoke macrophage apoptosis [24][25][26].…”

“…The ectopic expression of PE_PGRS62 in M. smegmatis enhances its survival within THP-1 macrophages and reduces cell apoptosis. It has been observed that PE_PGRS62 can inhibit the endoplasmic reticulum (ER) stress response ( Table 1) by downregulating C/EBP homologous protein (CHOP) and the 78-kDa glucose-regulated protein (GRP78/Bip), which are essential pro-apoptotic factors in response to stress conditions [25]. Likewise, M. smegmatis-expressing PE_PGRS41 induces much lower THP-1 macrophage apoptosis than the M. smegmatis expressing vector.…”