Mycobacterium tuberculosis PE17 (Rv1646) promotes host cell apoptosis via host chromatin remodeling mediated by reduced H3K9me3 occupancy

Abo-Kadoum, M. A.; Assad, Mohammed; Ali, Kaisar; Uae, Moure; Nzaou, Stech A.E.; Gong, Zhizhong; Moaaz, Asmaa; Lambert, Nzungize; Eltoukhy, Adel; Xie, Jianping

doi:10.1016/j.micpath.2021.105147

Cited by 10 publications

(3 citation statements)

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“…The members of the ESX-I and ESX-V secretory systems of Mtb have been shown to trigger host cell apoptosis that have implication on pathogen persistence [ 70 – 72 ]. Interestingly, the PE family proteins have co-evolved with the ESX-V secretory system and several PE family proteins such as PE9-PE10, PE_PGRS5, PE_PGRS33 and PE17 have been reported to induce apoptosis [ 9 , 10 , 73 – 75 ]. While apoptogenic function played by some of these proteins (PE_PGRS5 and PE17) was confirmed to be beneficial for bacilli survival that may facilitate infection persistence [ 50 , 76 ]; the apoptosis-inducing potential of others (such as PE9-PE10 and PE_PGRS33) have been discussed to be associated with pathogen survival rather than its killing [ 9 , 73 ].…”

Section: Discussionmentioning

confidence: 99%

Role of C-terminal domain of Mycobacterium tuberculosis PE6 (Rv0335c) protein in host mitochondrial stress and macrophage apoptosis

et al. 2022

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PE/PPE proteins of Mycobacterium tuberculosis (Mtb) target the host organelles to dictate the outcome of infection. This study investigated the significance of PE6/Rv0335c protein's unique C-terminal in causing host mitochondrial perturbations and apoptosis. In-silico analysis revealed that similar to eukaryotic apoptotic Bcl2 proteins, Rv0335c had disordered, hydrophobic C-terminal and two BH3-like motifs in which one was located at C-terminal. Also, Rv0335c’s N terminal had mitochondrial targeting sequence. Since, C-terminal of Bcl2 proteins are crucial for mitochondria targeting and apoptosis; it became relevant to evaluate the role of Rv0335c’s C-terminal domain in modulating host mitochondrial functions and apoptosis. To confirm this, in-vitro experiments were conducted with Rv0335c whole protein and Rv0335c∆Cterm (C-terminal domain deleted Rv0335c) protein. Rv0335c∆Cterm caused significant reduction in mitochondrial perturbations and Caspase-mediated apoptosis of THP1 macrophages in comparison to Rv0335c. However, the deletion of C-terminal domain didn’t affect Rv0335c’s ability to localize to mitochondria. Nine Ca 2+ binding residues were predicted within Rv0335c and four of them were at the C-terminal. In-vitro studies confirmed that Rv0335c caused significant increase in intracellular calcium influx whereas Rv0335c∆Cterm had insignificant effect on Ca 2+ influx. Rv0335c has been reported to be a TLR4 agonist and, we observed a significant reduction in the expression of TLR4-HLA-DR-TNF-α in response to Rv0335c∆Cterm protein also suggesting the role of Rv0335c’s C-terminal domain in host–pathogen interaction. These findings indicate the possibility of Rv0335c as a molecular mimic of eukaryotic Bcl2 proteins which equips it to cause host mitochondrial perturbations and apoptosis that may facilitate pathogen persistence. Supplementary Information The online version contains supplementary material available at 10.1007/s10495-022-01778-1.

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Section: Discussionmentioning

confidence: 99%

Role of C-terminal domain of Mycobacterium tuberculosis PE6 (Rv0335c) protein in host mitochondrial stress and macrophage apoptosis

et al. 2022

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“…Other hub-central genes of the pink module were included CCL8 ( Rusk et al, 2017 ), CCL20 ( Malone et al, 2018 ), CXCL3 ( Zhang et al, 2019 ), DUSP1 ( Abo-Kadoum et al, 2021 ), EDN1 ( Lin et al, 2015 ), ICAM1 ( Li P. et al, 2017 ), IER3 ( Widdison et al, 2011 ), ISG15 ( Kimmey et al, 2017 ), MAP3K8 ( Naeem et al, 2021 ), NFKBIA ( Tsai et al, 2009 ), NFKBIZ ( Dong et al, 2022 ), PTGS2 ( Xiong et al, 2018 ), PTX3 ( Wang et al, 2013 ), RSAD2 ( Andreu et al, 2017 ), TBK1 ( Wang J. et al, 2018 ), MAPK8 ( Gautam et al, 2014 ), BIRC3 ( MacHugh et al, 2012 ), TNFAIP3 ( Hall et al, 2020 ), TNFAIP6 ( Lin et al, 2015 ), and VEDFA ( Ndlovu and Marakalala, 2016 ), and the intracellular pathogen of MTBC such as M. bovis , could induce various strategies to escape the host immune response by activating or suppressing these genes. According to the literature reports on models of M. tuberculosis and M. bovis infection, some of these molecular mechanisms that contribute to the TB pathogenesis include the following:…”

Section: Discussionmentioning

confidence: 99%

In-depth systems biological evaluation of bovine alveolar macrophages suggests novel insights into molecular mechanisms underlying Mycobacterium bovis infection

et al. 2022

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ObjectiveBovine tuberculosis (bTB) is a chronic respiratory infectious disease of domestic livestock caused by intracellular Mycobacterium bovis infection, which causes ~$3 billion in annual losses to global agriculture. Providing novel tools for bTB managements requires a comprehensive understanding of the molecular regulatory mechanisms underlying the M. bovis infection. Nevertheless, a combination of different bioinformatics and systems biology methods was used in this study in order to clearly understand the molecular regulatory mechanisms of bTB, especially the immunomodulatory mechanisms of M. bovis infection.MethodsRNA-seq data were retrieved and processed from 78 (39 non-infected control vs. 39 M. bovis-infected samples) bovine alveolar macrophages (bAMs). Next, weighted gene co-expression network analysis (WGCNA) was performed to identify the co-expression modules in non-infected control bAMs as reference set. The WGCNA module preservation approach was then used to identify non-preserved modules between non-infected controls and M. bovis-infected samples (test set). Additionally, functional enrichment analysis was used to investigate the biological behavior of the non-preserved modules and to identify bTB-specific non-preserved modules. Co-expressed hub genes were identified based on module membership (MM) criteria of WGCNA in the non-preserved modules and then integrated with protein–protein interaction (PPI) networks to identify co-expressed hub genes/transcription factors (TFs) with the highest maximal clique centrality (MCC) score (hub-central genes).ResultsAs result, WGCNA analysis led to the identification of 21 modules in the non-infected control bAMs (reference set), among which the topological properties of 14 modules were altered in the M. bovis-infected bAMs (test set). Interestingly, 7 of the 14 non-preserved modules were directly related to the molecular mechanisms underlying the host immune response, immunosuppressive mechanisms of M. bovis, and bTB development. Moreover, among the co-expressed hub genes and TFs of the bTB-specific non-preserved modules, 260 genes/TFs had double centrality in both co-expression and PPI networks and played a crucial role in bAMs-M. bovis interactions. Some of these hub-central genes/TFs, including PSMC4, SRC, BCL2L1, VPS11, MDM2, IRF1, CDKN1A, NLRP3, TLR2, MMP9, ZAP70, LCK, TNF, CCL4, MMP1, CTLA4, ITK, IL6, IL1A, IL1B, CCL20, CD3E, NFKB1, EDN1, STAT1, TIMP1, PTGS2, TNFAIP3, BIRC3, MAPK8, VEGFA, VPS18, ICAM1, TBK1, CTSS, IL10, ACAA1, VPS33B, and HIF1A, had potential targets for inducing immunomodulatory mechanisms by M. bovis to evade the host defense response.ConclusionThe present study provides an in-depth insight into the molecular regulatory mechanisms behind M. bovis infection through biological investigation of the candidate non-preserved modules directly related to bTB development. Furthermore, several hub-central genes/TFs were identified that were significant in determining the fate of M. bovis infection and could be promising targets for developing novel anti-bTB therapies and diagnosis strategies.

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“…The pathogen persists and replicates intracellularly, and eventually Mtb-infected macrophages undergo two general modes of cell death: apoptosis and necrosis, both of which are observed not only in vitro (Behar et al, 2010), but also in macrophages in bronchoalveolar lavage (BAL) fluids and lungs of Mtb-infected animals (Martin et al, 2012;Repasy et al, 2013), as well as in human lung granulomas, which are hallmarks of TB lesions (Keane et al, 1997). To date, multiple inducers of apoptosis derived from Mtb have been identified (Mohareer et al, 2018;Yan et al, 2019;Abo-Kadoum et al, 2021;Lee et al, 2021;Sharma et al, 2021). Previous studies have suggested that a major mechanism linking Mtb virulence is the inhibition of macrophage apoptosis, enabling maintenance of a replicative niche for Mtb and preventing them from encountering host immune systems (Keane et al, 2000;Sly et al, 2003;Gan et al, 2008;Schaaf et al, 2017;Arnett et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Mycobacterial protein PE_PGRS30 induces macrophage apoptosis through prohibitin 2 mitochondrial function interference

Matsumura

Takaki²,

Kirikae³

2023

Front. Microbiol.

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PE_PGRS30 belongs to the PE_PGRS protein family and is characterized by a conserved Pro-Glu (PE) domain and a typically polymorphic GC-rich sequence (PGRS) domain. PE_PGRS30 is a virulence factor of Mycobacterium tuberculosis that induces macrophage cell death. We found that RAW264.7 cells and murine alveolar macrophages underwent apoptosis in response to PE_PGRS30. The host protein prohibitin 2 (PHB2) was identified as a target molecule. PE_PGRS30 and PHB2 interact via the PGRS domain and mitochondrial targeting sequence, respectively. PHB2 overexpression reduced macrophage apoptosis in response to PE_PGRS30. PE_PGRS30 co-localized with PHB2, not in mitochondria, but in lysosomes. The maintenance of mitochondrial structure by PHB2 was impaired in response to the PGRS domain. These results indicated that PE_PGRS30 reduces PHB2 in mitochondria, resulting in mitochondrial dysfunction and cellular apoptosis.

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Mycobacterium tuberculosis PE17 (Rv1646) promotes host cell apoptosis via host chromatin remodeling mediated by reduced H3K9me3 occupancy

Cited by 10 publications

References 64 publications

Role of C-terminal domain of Mycobacterium tuberculosis PE6 (Rv0335c) protein in host mitochondrial stress and macrophage apoptosis

Role of C-terminal domain of Mycobacterium tuberculosis PE6 (Rv0335c) protein in host mitochondrial stress and macrophage apoptosis

In-depth systems biological evaluation of bovine alveolar macrophages suggests novel insights into molecular mechanisms underlying Mycobacterium bovis infection

Mycobacterial protein PE_PGRS30 induces macrophage apoptosis through prohibitin 2 mitochondrial function interference

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