Mcl-1 Is a Key Regulator of Apoptosis Resistance in Chlamydia trachomatis-Infected Cells

Abstract

Chlamydia are obligate intracellular bacteria that cause variety of human diseases. Host cells infected with Chlamydia are protected against many different apoptotic stimuli. The induction of apoptosis resistance is thought to be an important immune escape mechanism allowing Chlamydia to replicate inside the host cell. Infection with C. trachomatis activates the Raf/MEK/ERK pathway and the PI3K/AKT pathway. Here we show that inhibition of these two pathways by chemical inhibitors sensitized C. trachomatis infected cells to granzyme B-mediated cell death. Infection leads to the Raf/MEK/ERK-mediated up-regulation and PI3K-dependent stabilization of the anti-apoptotic Bcl-2 family member Mcl-1. Consistently, interfering with Mcl-1 up-regulation sensitized infected cells for apoptosis induced via the TNF receptor, DNA damage, granzyme B and stress. Our data suggest that Mcl-1 up-regulation is primarily required to maintain apoptosis resistance in C. trachomatis-infected cells.

Tarp regulates earlyChlamydia-induced host cell survival through interactions with the human adaptor protein SHC1

“…We found pronounced activation of MEK and ERK shortly after infection coincident with phosphorylation of Tarp and SHC1. Previous work suggested that rapid phosphorylation of ERK during chlamydial infection is linked to up-regulation of the anti-apoptotic protein MCL-1 (Rajalingam et al, 2008), which we found to be independent of SHC1 (unpublished data). Moreover, in our previous work, activation of both MEK and ERK was shown to be necessary for C. trachomatis at an advanced stage of infection; however, this activation was uncoupled from upstream signaling by RAS and RAF (Gurumurthy et al, 2010).…”

“…In addition, Chlamydia subverts the function of the pro-apoptotic PKC by increasing diacylglycerol levels in the chlamydial inclusion membrane (Tse et al, 2005). Together, these observations suggest that Chlamydia prevents host cell apoptosis through a variety of mechanisms, likely acting sequentially as infection proceeds (Fan et al, 1998;Perfettini et al, 2002;Rajalingam et al, 2008). …”

“…Anti-apoptotic activity is thought to be conveyed by the proteolytic degradation of the pro-apoptotic BH3-only proteins BIM/BOD and PUMA and by the mitochondrial sequestration of BAD during chlamydial infection . Alternatively, recent studies have implicated the anti-apoptotic BCL-2 family member MCL-1 as a key factor in preventing apoptosis (Rajalingam et al, 2008). In addition, Chlamydia subverts the function of the pro-apoptotic PKC by increasing diacylglycerol levels in the chlamydial inclusion membrane (Tse et al, 2005).…”

“…C. trachomatis infection leads to extracellular signal-regulated kinase (ERK) activation, followed by the downstream activation of cytosolic phospholipase A2 (cPLA2; Su et al, 2004), the induction of interleukin-8 (IL-8; Buchholz and Stephens, 2008), TNF receptor 1 (TNFR1) shedding (Paland et al, 2008), and stabilization of MCL-1 (Rajalingam et al, 2008). Recent work has revealed that MEK (MAPK/ERK kinase)/ERK activation is independent of RAS/RAF during mid and late C. trachomatis infection (Gurumurthy et al, 2010).…”

Chlamydial Intracellular Survival Strategies

“…These differences will need to be reconciled in the future. In parallel, infection also leads to stabilization of IAP2 (inhibitor of apoptosis protein 2) and up-regulation of the prosurvival factor Mcl-1 (myeoloid cell leukemia) (Rajalingam et al 2006(Rajalingam et al , 2008Sharma et al 2011). Other mechanisms potentially include sequestration of Bad at the inclusion via 14-3-3b, and of protein kinase C-d (PKCd) through binding to diacylglycerol-enriched membranes in the vicinity of the inclusion (Scidmore and Hackstadt 2001;Tse et al 2005;Verbeke et al 2006). )…”