MicroRNA-302a suppresses influenza A virus–stimulated interferon regulatory factor-5 expression and cytokine storm induction

Chen, Xueyuan; Zhou, Li; Peng, Nanfang; Yu, Haisheng; Li, Mengqi; Cao, Zhongying; Lin, Yong; Wang, Xueyu; Li, Qian; Wang, Jun; She, Yuanbin; Zhu, Chengliang; Lu, Mengji; Zhu, Ying; Shi, Liyi

doi:10.1074/jbc.m117.805937

Cited by 60 publications

(45 citation statements)

References 42 publications

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“…Nevertheless, the overall effect of OGT in the IAV-induced cytokine storm remains unknown. We recently reported that IAV induces cytokine storm via interferon (IFN) regulatory factor-5 (IRF5) (19). In this study, we found that genetic deletion of OGT markedly impaired IAV-induced cytokine storm in vivo and in vitro.…”

Section: Introductionmentioning

confidence: 81%

“…IRF5, a member of the IRF family, is critical for regulating immune and inflammatory responses in health and disease (19). IRF5 contains a DNA binding domain, an IRF-association domain, and a serinerich region (SRR) at the C terminus (33).…”

Section: Discussionmentioning

confidence: 99%

“…S3A). In our previous studies, IRF5 was shown to be critical for IAV-induced cytokine storm (19). We hypothesized that OGT regulated IAV-induced cytokine storm via interacting with IRF5.…”

Section: Irf5 Is O-glcnacylated At S430 During Iav Infectionmentioning

confidence: 93%

“…Co-IP analyses were performed as previously described (19). Briefly, after treatment, cells were collected and lysed using lysis buffer [20 mM tris (pH 7), 0.5% (v/v) Nonidet-P40, 25 mM NaCl, 3 mM EDTA, 3 mM EGTA, 2 mM dithiothreitol, 0.5 mM phenylmethyl sulfonyl fluoride, 20 mM -glycerol phosphate, 1 mM sodium vanadate, and leupeptin (1 mg/ml)].…”

Section: Coimmunoprecipitationmentioning

confidence: 99%

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O -GlcNAc transferase promotes influenza A virus–induced cytokine storm by targeting interferon regulatory factor–5

et al. 2020

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In this study, we demonstrated an essential function of the hexosamine biosynthesis pathway (HBP)–associated O-linked β-N-acetylglucosamine (O-GlcNAc) signaling in influenza A virus (IAV)–induced cytokine storm. O-GlcNAc transferase (OGT), a key enzyme for protein O-GlcNAcylation, mediated IAV-induced cytokine production. Upon investigating the mechanisms driving this event, we determined that IAV induced OGT to bind to interferon regulatory factor–5 (IRF5), leading to O-GlcNAcylation of IRF5 on serine-430. O-GlcNAcylation of IRF5 is required for K63-linked ubiquitination of IRF5 and subsequent cytokine production. Analysis of clinical samples revealed that IRF5 is O-GlcNAcylated, and higher levels of proinflammatory cytokines correlated with higher levels of blood glucose in IAV-infected patients. We identified a molecular mechanism by which HBP-mediated O-GlcNAcylation regulates IRF5 function during IAV infection, highlighting the importance of glucose metabolism in IAV-induced cytokine storm.

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Section: Introductionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

“…S3A). In our previous studies, IRF5 was shown to be critical for IAV-induced cytokine storm (19). We hypothesized that OGT regulated IAV-induced cytokine storm via interacting with IRF5.…”

Section: Irf5 Is O-glcnacylated At S430 During Iav Infectionmentioning

confidence: 93%

Section: Coimmunoprecipitationmentioning

confidence: 99%

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O -GlcNAc transferase promotes influenza A virus–induced cytokine storm by targeting interferon regulatory factor–5

et al. 2020

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“…miRNAs have been shown to play key roles in the regulation of IAV-induced inflammatory response by controlling the pro-inflammatory intracellular signaling pathways. miR-302a is known to inhibit IAV replication by controlling interferon regulatory factor-5 (IRF-5) expression and cytokine storm induction [46]. Upregulation of miR-4776 in Influenza Virus infected primary human bronchial epithelial cells suppress IκB β, which further promotes cell survival [47].…”

Section: Discussionmentioning

confidence: 99%

Upregulation of miR-101 during Influenza A Virus Infection Abrogates Viral Life Cycle by Targeting mTOR Pathway

Sharma

Chatterjee

Kumar

et al. 2020

Viruses

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Micro RNAs (miRNAs) are a class of small non-coding single-stranded RNA, which play an important role in modulating host-Influenza A virus (IAV) crosstalk. The interplay between influenza and miRNA interaction is defined by a plethora of complex mechanisms, which are not fully understood yet. Here, we demonstrate that in IAV infected A549 cells, a synchronous increase was observed in the expression of mTOR up to 24 hpi and significant downregulation at 48 hpi. Additionally, NP of IAV interacts with mTOR and modulates the levels of mTOR mRNA and protein, thus regulating the translation of host cell. RNA sequencing and qPCR analysis of IAV-infected A549 cells and NP transfected cells revealed that miR-101 downregulates mTOR transcripts at later stages of infection. Ectopic expression of miR-101 mimic led to a decrease in expression of NP, a reduction in IAV titer and replication. Moreover, treatment of the cells with Everolimus, a potent inhibitor of mTOR, resulted in an increase of miR-101 transcript levels, which further suppressed the viral protein synthesis. Collectively, the data suggest a novel mechanism that IAV stimulates mTOR pathway at early stages of infection; however, at a later time-point, positive regulation of miR-101 restrains the mTOR expression, and hence, the viral propagation.

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Therapeutic Potential of Extracellular Vesicles for Sepsis Treatment

Kronstadt

Pottash

Levy

et al. 2021

Advanced Therapeutics

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Sepsis is a deadly condition lacking a specific treatment despite decades of research. This has prompted the exploration of new approaches, with extracellular vesicles (EVs) emerging as a focal area. EVs are nanosized, cell-derived particles that transport bioactive components (i.e., proteins, DNA, and RNA) between cells, enabling both normal physiological functions and disease progression depending on context. In particular, EVs have been identified as critical mediators of sepsis pathophysiology. However, EVs are also thought to constitute the biologically active component of cell-based therapies and have demonstrated anti-inflammatory, anti-apoptotic, and immunomodulatory effects in sepsis models. The dual nature of EVs in sepsis is explored here, discussing their endogenous roles and highlighting their therapeutic properties and potential. Related to the latter component, prior studies involving EVs from mesenchymal stem/stromal cells (MSCs) and other sources are discussed and emerging producer cells that could play important roles in future EV-based sepsis therapies are identified. Further, how methodologies could impact therapeutic development toward sepsis treatment to enhance and control EV potency is described.

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MicroRNA-302a suppresses influenza A virus–stimulated interferon regulatory factor-5 expression and cytokine storm induction

Cited by 60 publications

References 42 publications

O -GlcNAc transferase promotes influenza A virus–induced cytokine storm by targeting interferon regulatory factor–5

O -GlcNAc transferase promotes influenza A virus–induced cytokine storm by targeting interferon regulatory factor–5

Upregulation of miR-101 during Influenza A Virus Infection Abrogates Viral Life Cycle by Targeting mTOR Pathway

Therapeutic Potential of Extracellular Vesicles for Sepsis Treatment

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