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1.
Nat Microbiol ; 4(8): 1378-1388, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31110366

RESUMO

Mycobacterium tuberculosis (Mtb)-derived components are usually recognized by pattern recognition receptors to initiate a cascade of innate immune responses. One striking characteristic of Mtb is their utilization of different type VII secretion systems to secrete numerous proteins across their hydrophobic and highly impermeable cell walls, but whether and how these Mtb-secreted proteins are sensed by host immune system remains largely unknown. Here, we report that MPT53 (Rv2878c), a secreted disulfide-bond-forming-like protein of Mtb, directly interacts with TGF-ß-activated kinase 1 (TAK1) and activates TAK1 in a TLR2- or MyD88-independent manner. MPT53 induces disulfide bond formation at C210 on TAK1 to facilitate its interaction with TRAFs and TAB1, thus activating TAK1 to induce the expression of pro-inflammatory cytokines. Furthermore, MPT53 and its disulfide oxidoreductase activity is required for Mtb to induce the host inflammatory responses via TAK1. Our findings provide an alternative pathway for host signalling proteins to sense Mtb infection and may favour the improvement of current vaccination strategies.

2.
Nature ; 563(7729): 131-136, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30356214

RESUMO

Accurate repair of DNA double-stranded breaks by homologous recombination preserves genome integrity and inhibits tumorigenesis. Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that activates innate immunity by initiating the STING-IRF3-type I IFN signalling cascade1,2. Recognition of ruptured micronuclei by cGAS links genome instability to the innate immune response3,4, but the potential involvement of cGAS in DNA repair remains unknown. Here we demonstrate that cGAS inhibits homologous recombination in mouse and human models. DNA damage induces nuclear translocation of cGAS in a manner that is dependent on importin-α, and the phosphorylation of cGAS at tyrosine 215-mediated by B-lymphoid tyrosine kinase-facilitates the cytosolic retention of cGAS. In the nucleus, cGAS is recruited to double-stranded breaks and interacts with PARP1 via poly(ADP-ribose). The cGAS-PARP1 interaction impedes the formation of the PARP1-Timeless complex, and thereby suppresses homologous recombination. We show that knockdown of cGAS suppresses DNA damage and inhibits tumour growth both in vitro and in vivo. We conclude that nuclear cGAS suppresses homologous-recombination-mediated repair and promotes tumour growth, and that cGAS therefore represents a potential target for cancer prevention and therapy.

3.
Emerg Microbes Infect ; 7(1): 34, 2018 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-29559631

RESUMO

Tuberculosis caused by Mycobacterium tuberculosis (Mtb) infection remains a large global public health problem. One striking characteristic of Mtb is its ability to adapt to hypoxia and trigger the ensuing transition to a dormant state for persistent infection, but how the hypoxia response of Mtb is regulated remains largely unknown. Here we performed a quantitative acetylome analysis to compare the acetylation profile of Mtb under aeration and hypoxia, and showed that 377 acetylation sites in 269 Mtb proteins were significantly changed under hypoxia. In particular, deacetylation of dormancy survival regulator (DosR) at K182 promoted the hypoxia response in Mtb and enhanced the transcription of DosR-targeted genes. Mechanistically, recombinant DosRK182R protein demonstrated enhanced DNA-binding activity in comparison with DosRK182Q protein. Moreover, Rv0998 was identified as an acetyltransferase that mediates the acetylation of DosR at K182. Deletion of Rv0998 also promoted the adaptation of Mtb to hypoxia and the transcription of DosR-targeted genes. Mice infected with an Mtb strain containing acetylation-defective DosRK182R had much lower bacterial counts and less severe histopathological impairments compared with those infected with the wild-type strain. Our findings suggest that hypoxia induces the deacetylation of DosR, which in turn increases its DNA-binding ability to promote the transcription of target genes, allowing Mtb to shift to dormancy under hypoxia.


Assuntos
Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Lisina/metabolismo , Mycobacterium tuberculosis/metabolismo , Oxigênio/metabolismo , Proteínas Quinases/química , Proteínas Quinases/metabolismo , Tuberculose/microbiologia , Acetilação , Motivos de Aminoácidos , Proteínas de Bactérias/genética , Regulação Bacteriana da Expressão Gênica , Humanos , Mycobacterium tuberculosis/química , Mycobacterium tuberculosis/genética , Proteínas Quinases/genética
4.
J Huazhong Univ Sci Technolog Med Sci ; 36(3): 422-427, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27376815

RESUMO

The purpose of this research was to evaluate the structural stress and deformation of a newly designed onplant miniplate anchorage system compared to a standard anchorage system. A bone block integrated with a novel miniplate and fixation screw system was simulated in a three-dimensional model and subjected to force at different directions. The stress distribution and deformation of the miniplate system and cortical bone were evaluated using the three-dimensional finite element method. The results showed that the stress on the plate system and bone was linearly proportional to the force magnitude and was higher when the force was in a vertical direction (Y-axis). Stress and deformation values of the two screws (screw 1 and 2) were asymmetric when the force was added along Y-axis and was greater in screw 1. The highest deformation value of the screws was 7.5148 µm, much smaller than the limit value. The load was decreased for each single miniscrew, and the ability of the new anchorage system to bear the load was also enhanced to some degree. It was suggested that the newly designed onplant miniplate anchorage system is effective, easily implanted and minimally invasive.


Assuntos
Placas Ósseas , Parafusos Ósseos , Análise de Elementos Finitos , Imagem Tridimensional/métodos , Procedimentos de Ancoragem Ortodôntica/instrumentação , Fenômenos Biomecânicos , Osso Esponjoso/anatomia & histologia , Osso Esponjoso/cirurgia , Simulação por Computador , Osso Cortical/anatomia & histologia , Osso Cortical/cirurgia , Humanos , Procedimentos de Ancoragem Ortodôntica/métodos , Estresse Mecânico
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