Mycobacterium tuberculosisPPE32 promotes cytokines production and host cell apoptosis through caspase cascade accompanying with enhanced ER stress response

// Wanyan Deng 1, 2, * , Wenmin Yang 1, * , Jie Zeng 1 , Abualgasim Elgaili Abdalla 1, 3 , Jianping Xie 1 1 State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-Environments in Three Gorges Reservoir Region, Ministry of Education, School of Life Sciences, Institute of Modern Biopharmaceuticals, Southwest University, Chongqing, PR China 2 Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China 3 Department of Clinical Microbiology, College of Medical Laboratory Sciences, Omdurman Islamic University, Omdurman, Khartoum, Sudan * These authors contributed equally to this work Correspondence to: Jianping Xie, email: georgex@swu.edu.cn Keywords: Mycobacterium tuberculosis, PE/PPE, macrophage, apoptosis, caspase Received: May 09, 2016      Accepted: August 25, 2016      Published: September 15, 2016 ABSTRACT Tuberculosis, caused by Mycobacterium tuberculosis (MTB) infection, remains a grave global public health burden which claims the lives around two to three million annually. PE and PPE proteins, featured by the Pro-Glu (PE) or Pro-Pro-Glu (PPE) motifs at the conserved N-terminal domain, are abundant in the MTB genome. PPE32 can increase intracellular survival of mycobacteria through abnormally increase in cytokines production. PPE32 might subvert the macrophage immune response and thwart its bactericidal effect. THP-1 macrophages treated with PPE32 or infected with Mycobacterium smegmatis (MS) expression PPE32 showed increase of cytokines production and multiple hallmarks of apoptosis. We found that PPE32 significantly increases the expression of IL-12p40 and IL-32 through ERK1/2 signaling pathway. In addition, the cell viability of macrophage was inhibited after PPE32 stimulation. We noted that PPE32 induces cleavage of caspase-3 and caspase-9, while inhibition of caspase activity significantly abrogates the PPE32-induced cell apoptosis. Moreover, PPE32 treatment promotes endoplasmic reticulum stress related gene expression, suggesting ER stress might be responsible for PPE32-induced cell apoptosis.