The Transcriptional Foundations of Sp110-mediated Macrophage (RAW264.7) Resistance to Mycobacterium tuberculosis H37Ra

Wu, Yongyan; Guo, Zekun; Yao, Kezhen; Miao, Yuqing; Liang, Shuxin; Liu, Fayang; Wang, Yongsheng; Zhang, Yong

doi:10.1038/srep22041

Cited by 26 publications

(35 citation statements)

References 53 publications

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“…Our group recently performed small RNA sequencing and found that M. tuberculosis H37Ra (H37Ra) induced the expression of the cluster of miR-23b/27b (11). We hypothesized that the cluster of miR-23b/miR-27b/miR-24-1 could be regulated by M. tuberculosis.…”

Section: Mir-27b Is Upregulated Post-m Tuberculosis Infectionmentioning

confidence: 99%

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MicroRNA-27b Modulates Inflammatory Response and Apoptosis duringMycobacterium tuberculosisInfection

Liang

Song

et al. 2018

The Journal of Immunology

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poses a significant global health threat. MicroRNAs play an important role in regulating host anti-mycobacterial defense; however, their role in apoptosis-mediated mycobacterial elimination and inflammatory response remains unclear. In this study, we explored the role of microRNA-27b (miR-27b) in murine macrophage responses to infection. We uncovered that the TLR-2/MyD88/NF-κB signaling pathway induced the expression of miR-27b and miR-27b suppressed the production of proinflammatory factors and the activity of NF-κB, thereby avoiding an excessive inflammation during infection. Luciferase reporter assay and Western blotting showed that miR-27b directly targeted Bcl-2-associated athanogene 2 (Bag2) in macrophages. Overexpression of Bag2 reversed miR-27b-mediated inhibition of the production of proinflammatory factors. In addition, miR-27b increased p53-dependent cell apoptosis and the production of reactive oxygen species and decreased the bacterial burden. We also showed that Bag2 interacts with p53 and negatively regulates its activity, thereby controlling cell apoptosis and facilitating bacterial survival. In summary, we revealed a novel role of the miR-27b/Bag2 axis in the regulation of inflammatory response and apoptosis and provide a potential molecular host defense mechanism against mycobacteria.

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Section: Mir-27b Is Upregulated Post-m Tuberculosis Infectionmentioning

confidence: 99%

“…We previously investigated the role of miRNAs in M. tuberculosis H37Ra infection using small RNA sequencing, which suggested that M. tuberculosis H37Ra induces the expression of miR-27b (11). In the current study, we investigated the potential role of miR-27b in regulating macrophage apoptosis and inflammatory response during M. tuberculosis infection.…”

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confidence: 96%

MicroRNA-27b Modulates Inflammatory Response and Apoptosis duringMycobacterium tuberculosisInfection

Liang

Song

et al. 2018

The Journal of Immunology

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“…More than 30% of the world population is infected with Mtb , but less than a tenth of these individuals is at risk of developing overt clinical symptoms [ 1 ], suggesting that the innate immune system plays a crucial role in the defense against Mtb . Previous studies found that mouse intracellular pathogen resistance 1 (Ipr1, also known as Speckled 110 KDa protein) mediates innate immunity to Mtb and that overexpression of Ipr1 limits bacterial proliferation and reactivates the apoptotic pathway of Mtb -infected mouse macrophages [ 2 , 3 ]. Moreover, polymorphisms of the human homologue of the mouse Ipr1 gene ( Sp110 ) are associated with tuberculosis susceptibility [ 4 – 6 ].…”

Section: Introductionmentioning

confidence: 99%

The Arginine/Lysine-Rich Element within the DNA-Binding Domain Is Essential for Nuclear Localization and Function of the Intracellular Pathogen Resistance 1

Yao

Chen

et al. 2016

PLoS ONE

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The mouse intracellular pathogen resistance 1 (Ipr1) gene plays important roles in mediating host immunity and previous work showed that it enhances macrophage apoptosis upon mycobacterium infection. However, to date, little is known about the regulation pattern of Ipr1 action. Recent studies have investigated the protein-coding genes and microRNAs regulated by Ipr1 in mouse macrophages, but the structure and the functional motif of the Ipr1 protein have yet to be explored. In this study, we analyzed the domains and functional motif of the Ipr1 protein. The resulting data reveal that Ipr1 protein forms a homodimer and that the Sp100-like domain mediates the targeting of Ipr1 protein to nuclear dots (NDs). Moreover, we found that an Ipr1 mutant lacking the classic nuclear localization signal (cNLS) also translocated into the nuclei, suggesting that the cNLS is not the only factor that directs Ipr1 nuclear localization. Additionally, mechanistic studies revealed that an arginine/lysine-rich element within the DNA-binding domain (SAND domain) is critical for Ipr1 binding to the importin protein receptor NPI-1, demonstrating that this element plays an essential role in mediating the nuclear localization of Ipr1 protein. Furthermore, our results show that this arginine/lysine-rich element contributes to the transcriptional regulation and apoptotic activity of Ipr1. These findings highlight the structural foundations of Ipr1 action and provide new insights into the mechanism of Ipr1-mediated resistance to mycobacterium.

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“…In contrast, Sp110c, detected specifically in human peripheral blood leukocytes and spleen, is known to activate RAR␣-mediated transcription (9,10). Sp110 is reported to be associated with the hepatic veno-occlusive disease with immunodeficiency (VODI) (11), acute promyelocytic leukemia (8), and tuberculosis (12)(13)(14)(15)(16). A study showed that Sp110b interacts with hepatitis C virus core protein and gets relocalized from the nucleus to the cytosol (mainly near the endoplasmic reticulum membranes).…”

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Host transcription factor Speckled 110 kDa (Sp110), a nuclear body protein, is hijacked by hepatitis B virus protein X for viral persistence

Sengupta

Das

Singh³

et al. 2017

Journal of Biological Chemistry

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Promyelocytic leukemia nuclear bodies (PML-NB) are sub-nuclear organelles that are the hub of numerous proteins. DNA/RNA viruses often hijack the cellular factors resident in PML-NBs to promote their proliferation in host cells. Hepatitis B virus (HBV), belonging to Hepadnaviridae family, remains undetected in early infection as it does not induce the innate immune response and is known to be the cause of several hepatic diseases leading to cirrhosis and hepatocellular carcinoma. The association of PML-NB proteins and HBV is being addressed in a number of recent studies. Here, we report that the PML-NB protein Speckled 110 kDa (Sp110) is SUMO1-modified and undergoes a deSUMOylation-driven release from the PML-NB in the presence of HBV. Intriguingly, Sp110 knockdown significantly reduced viral DNA load in the culture supernatant by activation of the type I interferon-response pathway. Furthermore, we found that Sp110 differentially regulates several direct target genes of hepatitis B virus protein X (HBx), a viral co-factor. Subsequently, we identified Sp110 as a novel interactor of HBx and found this association to be essential for the exit of Sp110 from the PML-NB during HBV infection and HBx recruitment on the promoter of these genes. HBx, in turn, modulates the recruitment of its associated transcription cofactors p300/HDAC1 to these co-regulated genes, thereby altering the host gene expression program in favor of viral persistence. Thus, we report a mechanism by which HBV can evade host immune response by hijacking the PML-NB protein Sp110, and therefore, we propose it to be a novel target for antiviral therapy.

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The Transcriptional Foundations of Sp110-mediated Macrophage (RAW264.7) Resistance to Mycobacterium tuberculosis H37Ra

Cited by 26 publications

References 53 publications

MicroRNA-27b Modulates Inflammatory Response and Apoptosis duringMycobacterium tuberculosisInfection

MicroRNA-27b Modulates Inflammatory Response and Apoptosis duringMycobacterium tuberculosisInfection

The Arginine/Lysine-Rich Element within the DNA-Binding Domain Is Essential for Nuclear Localization and Function of the Intracellular Pathogen Resistance 1

Host transcription factor Speckled 110 kDa (Sp110), a nuclear body protein, is hijacked by hepatitis B virus protein X for viral persistence

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