Unphosphorylated STAT1 represses apoptosis in macrophages during Mycobacterium t
 uberculosis infection

Yao, Kezhen; Chen, Qi; Wu, Yongyan; Liu, Fayang; Chen, Xin; Zhang, Yong

doi:10.1242/jcs.200659

Cited by 28 publications

(25 citation statements)

References 68 publications

(93 reference statements)

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“…Similarly, the expression of miR-27b was upregulated, and the endogenous expression of Bag2 was inhibited post-H37Ra infection, suggesting that M. tuberculosis-induced overexpression of miR-27b is associated with the inhibition of Bag2. Furthermore, recent studies have shown that Bag2 binds to Sp110 (a positive anti-mycobacterial regulator) (45) and unphosphorylated STAT1 (46) to alter the cell death pathway. These results indicate a critical role of Bag2 in modulating macrophage resistance to M. tuberculosis.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

MicroRNA-27b Modulates Inflammatory Response and Apoptosis duringMycobacterium tuberculosisInfection

Liang

Song

et al. 2018

The Journal of Immunology

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“…However, Yao et al recently observed in Mycobacterium tuberculosis (Mtb)-infected macrophages a rapid increase in phosphorylated STAT1, which quickly declined over a period of hours, but a continued increase of unphosphorylated U-STAT1 that persisted for several days. As such, U-STAT1 affected the expression of several immune-associated genes, and lowered sensitivity of macrophages to CD95-mediated apoptosis during Mtb infection ( 54 ). Likewise, Majoros et al showed the importance of U-STAT1 in IFN-I-induced gene expression regulation and biological activity in mice expressing a Stat1Y701F mutant ( 19 ).…”

Section: Unphosphorylated Stat1 and Stat2: U-isgf3 U-stat2/irf9 Andmentioning

confidence: 99%

A Positive Feedback Amplifier Circuit That Regulates Interferon (IFN)-Stimulated Gene Expression and Controls Type I and Type II IFN Responses

et al. 2018

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Interferon (IFN)-I and IFN-II both induce IFN-stimulated gene (ISG) expression through Janus kinase (JAK)-dependent phosphorylation of signal transducer and activator of transcription (STAT) 1 and STAT2. STAT1 homodimers, known as γ-activated factor (GAF), activate transcription in response to all types of IFNs by direct binding to IFN-II activation site (γ-activated sequence)-containing genes. Association of interferon regulatory factor (IRF) 9 with STAT1–STAT2 heterodimers [known as interferon-stimulated gene factor 3 (ISGF3)] or with STAT2 homodimers (STAT2/IRF9) in response to IFN-I, redirects these complexes to a distinct group of target genes harboring the interferon-stimulated response element (ISRE). Similarly, IRF1 regulates expression of ISGs in response to IFN-I and IFN-II by directly binding the ISRE or IRF-responsive element. In addition, evidence is accumulating for an IFN-independent and -dependent role of unphosphorylated STAT1 and STAT2, with or without IRF9, and IRF1 in basal as well as long-term ISG expression. This review provides insight into the existence of an intracellular amplifier circuit regulating ISG expression and controlling long-term cellular responsiveness to IFN-I and IFN-II. The exact timely steps that take place during IFN-activated feedback regulation and the control of ISG transcription and long-term cellular responsiveness to IFN-I and IFN-II is currently not clear. Based on existing literature and our novel data, we predict the existence of a multifaceted intracellular amplifier circuit that depends on unphosphorylated and phosphorylated ISGF3 and GAF complexes and IRF1. In a combinatorial and timely fashion, these complexes mediate prolonged ISG expression and control cellular responsiveness to IFN-I and IFN-II. This proposed intracellular amplifier circuit also provides a molecular explanation for the existing overlap between IFN-I and IFN-II activated ISG expression.

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“…Nevertheless, IFN-α has been consistently reported to selectively induce proinflammatory genes containing GAS in the absence of an ISRE [63][64][65][66][67]. Moreover, it has recently been evidenced that U-STAT1 persists in macrophages following pathogenic stimulation it and could induce immunomodulatory genes, in contrast to phosphorylated (p)-STAT1, which undergoes rapid degradation [68].…”

Section: Introductionmentioning

confidence: 99%

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

Owen

Brockwell

Parker

2019

Cancers

435

326

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Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates almost all immune regulatory processes, including those that are involved in tumor cell recognition and tumor-driven immune escape. Antitumor immune responses are largely driven by STAT1 and STAT2 induction of type I and II interferons (IFNs) and the downstream programs IFNs potentiate. Conversely, STAT3 has been widely linked to cancer cell survival, immunosuppression, and sustained inflammation in the tumor microenvironment. The discovery of JAK-STAT cross-regulatory mechanisms, post-translational control, and non-canonical signal transduction has added a new level of complexity to JAK-STAT governance over tumor initiation and progression. Endeavors to better understand the vast effects of JAK-STAT signaling on antitumor immunity have unearthed a wide range of targets, including oncogenes, miRNAs, and other co-regulatory factors, which direct specific phenotypical outcomes subsequent to JAK-STAT stimulation. Yet, the rapidly expanding field of therapeutic developments aimed to resolve JAK-STAT aberrations commonly reported in a multitude of cancers has been marred by off-target effects. Here, we discuss JAK-STAT biology in the context of immunity and cancer, the consequences of pathway perturbations and current therapeutic interventions, to provide insight and consideration for future targeting innovations.2 of 26 role in pathogenesis [3]. Yet, despite the seemingly linear order of events, the impact of mutations, selective dimerization, negative pathway regulation, and post-translational modifications of pathway members has branded the JAK-STAT axis a complex signaling cascade, of which many regulatory processes are still poorly understood.STATs have emerged as somewhat of a double-edged sword, being widely explored in the context of cancer. While several members of the STAT family, which encompasses STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6 as a whole, have been linked to tumor initiation and progression (STAT3 and STAT5), others are integral in antitumor defense and the maintenance of an effective and long-term immune response (STAT1 and STAT2) through evolutionarily conserved programs [1]. With increasing emphasis on immune-based agents as important therapeutics in the fight against solid tumor growth and spread, understanding the function of STAT specificity, redundancy, and connectedness in cancer is a critical component of achieving immunotherapeutic augmentation and success.Here, we investigate the good and the bad of STAT signaling in the context of immune regulation and cancer, and discuss how STATs can be targeted to bolster antitumor immune defense. JAK-STAT Signaling and InterferonsThe presence of stimulatory or inhibitory signals governs the innate and adaptive immune activity that controls both effective immune surveillance and facilitates escape. Such signals determine the fate of plastic immune cells, such as T lymphocytes, and regulate their recruitment, survival, status, and eventual death ...

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Unphosphorylated STAT1 represses apoptosis in macrophages during Mycobacterium t uberculosis infection

Cited by 28 publications

References 68 publications

MicroRNA-27b Modulates Inflammatory Response and Apoptosis duringMycobacterium tuberculosisInfection

MicroRNA-27b Modulates Inflammatory Response and Apoptosis duringMycobacterium tuberculosisInfection

A Positive Feedback Amplifier Circuit That Regulates Interferon (IFN)-Stimulated Gene Expression and Controls Type I and Type II IFN Responses

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

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