Calreticulin modulates the intracellular survival of mycobacteria by regulating ER-stress-mediated apoptosis
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Sung Hee Jo1,2,4,*, Ji-Ae Choi1,2,4,*, Yun-Ji Lim1,2,4, Junghwan Lee1,2,4, Soo-Na Cho1,2,4, Sung-Man Oh1,2,4, Dam Go1,2,4, Seon-Hwa Kim1,2,4 and Chang-Hwa Song1,2,3,4
1Department of Medical Science, Chungnam National University, Daejeon, Republic of Korea
2Department of Microbiology, Chungnam National University, Daejeon, Republic of Korea
3Research Institute for Medical Sciences, Chungnam National University, Daejeon, Republic of Korea
4College of Medicine, Chungnam National University, Daejeon, Republic of Korea
*These authors have contributed equally to this work
Chang-Hwa Song, email: firstname.lastname@example.org
Keywords: ER stress, apoptosis, mycobacteria, calreticulin, macrophages
Received: February 08, 2017 Accepted: March 28, 2017 Published: April 25, 2017
Endoplasmic reticulum (ER)-stress-mediated apoptosis is a host defense mechanism against Mycobacterium tuberculosis (Mtb) infection. Calreticulin (CRT) is the major calcium-binding chaperone protein. Previous reports have suggested a close relationship between the cell-surface expression of CRT and apoptosis. In this study, the role of CRT during Mtb infection was examined. The results showed that Mtb infection induces CRT production by macrophages and that CRT levels are correlated with the degree of apoptotic cell death. The enhanced production of CRT was associated with the ER stress induced by Mtb infection. A significant increase in CRT translocation from the cytosol to the plasma membrane after 24 h of infection suggested the importance of CRT localization in the induction of apoptosis during Mtb infection. An investigation of the factors associated with CRT translocation and the ability of ectopically expressed CRT to induce apoptosis showed that pretreatment with a reactive oxygen species scavenger decreased Mtb-induced CRT expression, leading to the reduction of CHOP and caspase-3 activation. The intracellular survival of Mtb was significantly higher in macrophages transfected with a CRT-specific small interfering RNA than in control cells. The key role of CRT in inducing apoptosis included its interaction with CXCR1 and TNFR1 in Mtb-infected macrophages. The CRT/CXCR1/TNFR1 complex was shown to induce the extrinsic apoptotic pathway during Mtb infection. Together, these results demonstrate that CRT is critical for the intracellular survival of Mtb, via ER-stress-induced apoptosis, as well as the importance of ER stress-mediated CRT localization in the pathogenesis of tuberculosis.
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