Mycobacterium tuberculosis Protein PE6 (Rv0335c), a Novel TLR4 Agonist, Evokes an Inflammatory Response and Modulates the Cell Death Pathways in Macrophages to Enhance Intracellular Survival.
Neha Sharma,Neha Sharma,Mohd Shariq,Neha Quadir,Neha Quadir,Jasdeep Singh,Javaid A. Sheikh,Seyed E. Hasnain,Seyed E. Hasnain,Nasreen Z. Ehtesham +9 more
TLDR
In this article, the authors show that PE6 protein (Rv0335c) is a secretory protein effector that interacts with TLR4 on the macrophage cell surface and promotes activation of the canonical NF-B signaling pathway to stimulate secretion of proinflammatory cytokines TNF-α, IL-12, and IL-6.Abstract:
Mycobacterium tuberculosis (M. tb) is an intracellular pathogen that exploits moonlighting functions of its proteins to interfere with host cell functions. PE/PPE proteins utilize host inflammatory signaling and cell death pathways to promote pathogenesis. We report that M. tb PE6 protein (Rv0335c) is a secretory protein effector that interacts with innate immune toll-like receptor TLR4 on the macrophage cell surface and promotes activation of the canonical NFĸB signaling pathway to stimulate secretion of proinflammatory cytokines TNF-α, IL-12, and IL-6. Using mouse macrophage TLRs knockout cell lines, we demonstrate that PE6 induced secretion of proinflammatory cytokines dependent on TLR4 and adaptor Myd88. PE6 possesses nuclear and mitochondrial targeting sequences and displayed time-dependent differential localization into nucleus/nucleolus and mitochondria, and exhibited strong Nucleolin activation. PE6 strongly induces apoptosis via increased production of pro-apoptotic molecules Bax, Cytochrome C, and pcMyc. Mechanistic details revealed that PE6 activates Caspases 3 and 9 and induces endoplasmic reticulum-associated unfolded protein response pathways to induce apoptosis through increased production of ATF6, Chop, BIP, eIF2α, IRE1α, and Calnexin. Despite being a potent inducer of apoptosis, PE6 suppresses innate immune defense strategy autophagy by inducing inhibitory phosphorylation of autophagy initiating kinase ULK1. Inversely, PE6 induces activatory phosphorylation of autophagy master regulator MtorC1, which is reflected by lower conversion of autophagy markers LC3BI to LC3BII and increased accumulation of autophagy substrate p62 which is also dependent on innate immune receptor TLR4. The use of pharmacological agents, rapamycin and bafilomycin A1, confirms the inhibitory effect of PE6 on autophagy, evidenced by the reduced conversion of LC3BI to LC3BII and increased accumulation of p62 in the presence of rapamycin and bafilomycin A1. We also observed that PE6 binds DNA, which could have significant implications in virulence. Furthermore, our analyses reveal that PE6 efficiently binds iron to likely aid in intracellular survival. Recombinant Mycobacterium smegmatis (M. smegmatis) containing pe6 displayed robust growth in iron chelated media compared to vector alone transformed cells, which suggests a role of PE6 in iron acquisition. These findings unravel novel mechanisms exploited by PE6 protein to subdue host immunity, thereby providing insights relevant to a better understanding of host-pathogen interaction during M. tb infection.read more
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The Role of TLR2 in Infectious Diseases Caused by Mycobacteria: From Cell Biology to Therapeutic Target
Wanbin Hu,Herman P. Spaink +1 more
TL;DR: In this paper , the authors summarize the knowledge of the functions of TLR2 in host-mycobacterial interactions, discuss controversial results, and suggest possibilities for future research.
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The exploitation of host autophagy and ubiquitin machinery by Mycobacterium tuberculosis in shaping immune responses and host defense during infection
M. Shariq,Neha Quadir,Anwar Alam,Sheeba Zarin,Javaid A. Sheikh,Neha Sharma,Jasmine Samal,Uzair Ahmad,Indu Kumari,Seyed E. Hasnain,Nasreen Z. Ehtesham +10 more
TL;DR: The role of E3-Ub ligases and their mode of autophagy regulation is discussed in this paper , which highlights the xenophagy-mediated clearance of Mycobacterium tuberculosis (M. tb) using virulence factors.
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The Mycobacterium tuberculosis PE_PGRS Protein Family Acts as an Immunological Decoy to Subvert Host Immune Response
Tarina Sharma,Anwar Alam,Aquib Ehtram,Anshu Rani,Sonam Grover,Nasreen Z. Ehtesham,Seyed E. Hasnain +6 more
TL;DR: The highly repetitive, redundant and antigenic nature of PE/PPE/PE_PGRS proteins provide a critical edge over other M.tb proteins in terms of imparting a higher level of virulence and also as a decoy molecule that masks the effect of effector molecules, thereby modulating immuno-surveillance.
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Mycobacterium tuberculosis PPE51 Inhibits Autophagy by Suppressing Toll-Like Receptor 2-Dependent Signaling
TL;DR: The results demonstrate a direct role of PPE51 for evasion of both innate and adaptive immunity to Mtb, and suggest that TLR2 activates relevant host immune functions during mycobacterial infection, which Mtb then evades through suppression ofTLR2 signaling by PPE 51.
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Can Mycobacterium tuberculosis infection lead to cancer? Call for a paradigm shift in understanding TB and cancer.
TL;DR: Roy et al. as mentioned in this paper investigated the role of Mycobacterium tuberculosis (M. tb) as a carcinogen in lung cancer and showed that M tb infection is a major risk factor for cancer.
References
More filters
Journal ArticleDOI
Inference of macromolecular assemblies from crystalline state.
E. Krissinel,Kim Henrick +1 more
TL;DR: A new method, based on chemical thermodynamics, is developed for automatic detection of macromolecular assemblies in the Protein Data Bank (PDB) entries that are the results of X-ray diffraction experiments, as found, biological units may be recovered at 80-90% success rate, which makesX-ray crystallography an important source of experimental data on macromolescular complexes and protein-protein interactions.
Journal ArticleDOI
Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence
Stewart T. Cole,Roland Brosch,Julian Parkhill,Thierry Garnier,Carol Churcher,David Harris,Stephen V. Gordon,Karin Eiglmeier,S. Gas,Clifton E. Barry,Fredj Tekaia,K. Badcock,D. Basham,D. Brown,Tracey Chillingworth,R. Connor,Robert L. Davies,K. Devlin,Theresa Feltwell,S. Gentles,N. Hamlin,S. Holroyd,T. Hornsby,Kay Jagels,Anders Krogh,J. McLean,Sharon Moule,Lee Murphy,K. Oliver,J. Osborne,Michael A. Quail,Marie-Adèle Rajandream,Jane Rogers,S. Rutter,K. Seeger,Jason Skelton,Rob Squares,S. Squares,John Sulston,K. Taylor,Sally Whitehead,Bart Barrell +41 more
TL;DR: The complete genome sequence of the best-characterized strain of Mycobacterium tuberculosis, H37Rv, has been determined and analysed in order to improve the understanding of the biology of this slow-growing pathogen and to help the conception of new prophylactic and therapeutic interventions.
Journal ArticleDOI
Defective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in Tlr4 Gene
Alexander Poltorak,Xiaolong He,Irina Smirnova,Mu Ya Liu,Christophe Van Huffel,Xin Du,Dale Birdwell,E. Alejos,M. Silva,Chris Galanos,Marina Freudenberg,Paola Ricciardi-Castagnoli,Betsy Layton,Bruce Beutler +13 more
TL;DR: The mammalian Tlr4 protein has been adapted primarily to subserve the recognition of LPS and presumably transduces the LPS signal across the plasma membrane.
Journal ArticleDOI
I-TASSER: a unified platform for automated protein structure and function prediction
TL;DR: The iterative threading assembly refinement (I-TASSER) server is an integrated platform for automated protein structure and function prediction based on the sequence- to-structure-to-function paradigm.
Journal ArticleDOI
AQUA and PROCHECK-NMR: programs for checking the quality of protein structures solved by NMR
TL;DR: The AQUA and PROCHECK-NMR programs provide a means of validating the geometry and restraint violations of an ensemble of protein structures solved by solution NMR, and their outputs include a detailed breakdown of the restraint violations.