Mycobacterium tuberculosis Rv2185c contributes to nuclear factor-κB activation

Zhang, Huan; Ouyang, Huiyi; Wang, Dan; Shi, Junwei; Ouyang, Cheng; Chen, Huanchun; Xiao, Shaobo; Fang, Liurong

doi:10.1016/j.molimm.2015.02.020

Cited by 11 publications

(9 citation statements)

References 37 publications

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“…In the present study, PAK and AKT were also activated in control RSFs compared with TIPE +/+ RSFs (37,38). Increased activation of NAK was also observed in control RSFs compared with TIPE2-overexpressed RSFs, indicating that TIPE2 regulates NAK via the Rac/PAK pathway (39,40).…”

Section: Discussionsupporting

confidence: 64%

Tumor necrosis factor-α-induced protein-8 like 2 regulates lipopolysaccharide-induced rat rheumatoid arthritis immune responses and is associated with Rac activation and interferon regulatory factor 3 phosphorylation

Shi

Wang

Zhuang

et al. 2017

Molecular Medicine Reports

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The endogenously activated rheumatoid arthritis (RA) synovial fibroblasts (RSFs) are likely to be the key to curing the disease. RSFs express Toll‑like receptors (TLRs) rendering them prone to activation by exogenous and endogenous TLR ligands, resulting in the production of chemokines and cytokines Germline deletion of tumor necrosis factor‑α‑induced protein‑8 like 2 (TIPE2, also known as TNFAIP8L2) results in fatal inflammation and hypersensitivity to TLR and T cell receptor stimulation. The present study demonstrates an inverse association between TIPE2 and cytokine gene expression in RSFs following lipopolysaccharide (LPS) stimulation. Enhanced TIPE2 expression decreased Ras‑related C3 botulinum toxin substrate (Rac) activation and interferon regulatory factor 3 phosphorylation, and phosphoinositide 3‑kinase and Rac inhibition significantly diminished LPS‑induced cytokine gene expression in RSFs. In conclusion, the findings of the present study demonstrate that TIPE2 serves a negative role in activating the Rac signaling pathway and in the initiation of the immune response by decreasing the activity of proinflammatory cytokines. These results may be useful in designing novel strategies for the prevention and treatment of RA.

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Section: Discussionsupporting

confidence: 64%

Tumor necrosis factor-α-induced protein-8 like 2 regulates lipopolysaccharide-induced rat rheumatoid arthritis immune responses and is associated with Rac activation and interferon regulatory factor 3 phosphorylation

Shi

Wang

Zhuang

et al. 2017

Molecular Medicine Reports

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“…Transcription factor NF-κB signaling pathways are reported to regulate innate immunity. Inflammatory cytokines, such as IL-6, IL-1β and TNF-α, are involved in activating cells of the immune system in response to mycobacterial infection [ 23 , 24 ]. Genes associated with the NF-κB pathway, were among the most strongly upregulated genes in Cas6-THP-1 cells ( Figure 5(c) , Supplementary Figure 5).…”

Section: Resultsmentioning

confidence: 99%

M. tuberculosis CRISPR/Cas proteins are secreted virulence factors that trigger cellular immune responses

et al. 2021

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The role of prokaryotic CRISPR/Cas system proteins as a defensive shield against invasive nucleic acids has been studied extensively. Non-canonical roles in pathogenesis involving intracellular targeting of certain virulence-associated endogenous mRNA have also been reported for some Type I and Type II CRISPR/Cas proteins, but no such roles have yet been established for Type III system proteins. Here, we demonstrate that M. tuberculosis (Type III-A system) CRISPR/Cas proteins Csm1, Csm3, Csm5, Csm6, and Cas6 are secreted and induce host immune responses. Using cell and animal experiments, we show that Cas6, in particular, provokes IFN-γ release from PBMCs from active tuberculosis (TB) patients, and its deletion markedly attenuates virulence in a murine M. tuberculosis challenge model. Recombinant MTBCas6 induces apoptosis of macrophages and lung fibroblasts, and interacts with the surface of cells in a caspase and TLR-2 independent manner. Transcriptomic and signal pathway studies using THP-1 macrophages stimulated with MTBCas6 indicated that MTBCas6 upregulates expression of genes associated with the NF-κB pathway leading to higher levels of IL-6, IL-1β, and TNF-α release, cytokines known to activate immune system cells in response to M. tuberculosis infection. Our findings suggest that, in addition to their intracellular shielding role, M. tuberculosis CRISPR/Cas proteins have non-canonical extracellular roles, functioning like a virulent sword, and activating host immune responses.

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“…Starck et al reported that in M. tuberculosis Rv2185c was over expressed under anaerobic conditions (Starck et al, 2004). It is reported that over expression of Rv2185c induced IκBα degradation and nuclear translocation of NFκB (Zhang et al, 2015). In the present study we have observed that AK and KM interacted to the residues of conserved Polyketide cyclase/dehydrase domain, which might alter the function.…”

Section: Discussionmentioning

confidence: 99%

Cytosolic Proteome Profiling of Aminoglycosides Resistant Mycobacterium tuberculosis Clinical Isolates Using MALDI-TOF/MS

et al. 2016

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Emergence of extensively drug resistant tuberculosis (XDR-TB) is the consequence of the failure of second line TB treatment. Aminoglycosides are the important second line anti-TB drugs used to treat the multi drug resistant tuberculosis (MDR-TB). Main known mechanism of action of aminoglycosides is to inhibit the protein synthesis by inhibiting the normal functioning of ribosome. Primary target of aminoglycosides are the ribosomal RNA and its associated proteins. Various mechanisms have been proposed for aminoglycosides resistance but still some are unsolved. As proteins are involved in most of the biological processes, these act as a potential diagnostic markers and drug targets. In the present study we analyzed the purely cytosolic proteome of amikacin (AK) and kanamycin (KM) resistant Mycobacterium tuberculosis isolates by proteomic and bioinformatic approaches. Twenty protein spots were found to have over expressed in resistant isolates and were identified. Among these Rv3208A, Rv2623, Rv1360, Rv2140c, Rv1636, and Rv2185c are six proteins with unknown functions or undefined role. Docking results showed that AK and KM binds to the conserved domain (DUF, USP-A, Luciferase, PEBP and Polyketidecyclase/dehydrase domain) of these hypothetical proteins and over expression of these proteins might neutralize/modulate the effect of drug molecules. TBPred and GPS-PUP predicted cytoplasmic nature and potential pupylation sites within these identified proteins, respectively. String analysis also suggested that over expressed proteins along with their interactive partners might be involved in aminoglycosides resistance. Cumulative effect of these over expressed proteins could be involved in AK and KM resistance by mitigating the toxicity, repression of drug target and neutralizing affect. These findings need further exploitation for the expansion of newer therapeutics or diagnostic markers against AK and KM resistance so that an extreme condition like XDR-TB can be prevented.

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Mycobacterium tuberculosis Rv2185c contributes to nuclear factor-κB activation

Cited by 11 publications

References 37 publications

Tumor necrosis factor-α-induced protein-8 like 2 regulates lipopolysaccharide-induced rat rheumatoid arthritis immune responses and is associated with Rac activation and interferon regulatory factor 3 phosphorylation

Tumor necrosis factor-α-induced protein-8 like 2 regulates lipopolysaccharide-induced rat rheumatoid arthritis immune responses and is associated with Rac activation and interferon regulatory factor 3 phosphorylation

M. tuberculosis CRISPR/Cas proteins are secreted virulence factors that trigger cellular immune responses

Cytosolic Proteome Profiling of Aminoglycosides Resistant Mycobacterium tuberculosis Clinical Isolates Using MALDI-TOF/MS

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