Regulation of gammaherpesvirus lytic replication by endoplasmic reticulum stress–induced transcription factors ATF4 and CHOP

Zhou, Xing; Dong, Sihan; Liu, Zhongshun; Liu, Shuai; Zhang, Chaocan; Liang, Xiaozhen

doi:10.1074/jbc.m117.813675

Cited by 15 publications

(13 citation statements)

References 53 publications

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“…Thus, PPARγ might have different roles in ROS production due to the physiological and pathological conditions. Numerous studies have suggested a central role of ERK1/2 and STAT3 signaling pathways in regulating oxidative stress and related cell apoptosis (18)(19)(20)(21). As expected, phosphorylation of ERK1/2 and STAT3 were increased after PM2.5 exposure.…”

Section: Discussionsupporting

confidence: 75%

Rosiglitazone inhibits PM2.5-induced cytotoxicity in human lung epithelial A549 cells

Zhou

et al. 2018

Ann. Transl. Med.

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Section: Discussionsupporting

confidence: 75%

Rosiglitazone inhibits PM2.5-induced cytotoxicity in human lung epithelial A549 cells

Zhou

et al. 2018

Ann. Transl. Med.

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“…Type I IFNindependent effects of STING include the upregulation of endoplasmic reticulum (ER) stress-associated autophagy (38), as well as the activation of NF-B (39), which can interact with TpI2/AP1 to promote lytic replication of ␥HV68 (40). Autophagy-related genes also promote lytic replication and reactivation of ␥HV68 from latency (41,42). Thus, in addition to impacting type I IFN signaling, STING N153S may have other effects that promote ␥HV68 replication independently of type I IFN.…”

Section: Discussionmentioning

confidence: 99%

A Human Gain-of-Function STING Mutation Causes Immunodeficiency and Gammaherpesvirus-Induced Pulmonary Fibrosis in Mice

Bennion

Ingle

et al. 2019

J Virol

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We previously generated STING N153S knock-in mice that have a human disease-associated gain-of-function mutation in STING. Patients with this mutation (STING N154S in humans) develop STING-associated vasculopathy with onset in infancy (SAVI), a severe pediatric autoinflammatory disease characterized by pulmonary fibrosis. Since this mutation promotes the upregulation of antiviral type I interferon-stimulated genes (ISGs), we hypothesized that STING N153S knock-in mice may develop more severe autoinflammatory disease in response to a virus challenge. To test this hypothesis, we infected heterozygous STING N153S mice with murine gammaherpesvirus 68 (γHV68). STING N153S mice were highly vulnerable to infection and developed pulmonary fibrosis after infection. In addition to impairing CD8+ T cell responses and humoral immunity, STING N153S also promoted the replication of γHV68 in cultured macrophages. In further support of a combined innate and adaptive immunodeficiency, γHV68 infection was more severe in Rag1–/– STING N153S mice than in Rag1–/– littermate mice, which completely lack adaptive immunity. Thus, a gain-of-function STING mutation creates a combined innate and adaptive immunodeficiency that leads to virus-induced pulmonary fibrosis. IMPORTANCE A variety of human rheumatologic disease-causing mutations have recently been identified. Some of these mutations are found in viral nucleic acid-sensing proteins, but whether viruses can influence the onset or progression of these human diseases is less well understood. One such autoinflammatory disease, called STING-associated vasculopathy with onset in infancy (SAVI), affects children and leads to severe lung disease. We generated mice with a SAVI-associated STING mutation and infected them with γHV68, a common DNA virus that is related to human Epstein-Barr virus. Mice with the human disease-causing STING mutation were more vulnerable to infection than wild-type littermate control animals. Furthermore, the STING mutant mice developed lung fibrosis similar to that of patients with SAVI. These findings reveal that a human STING mutation creates severe immunodeficiency, leading to virus-induced lung disease in mice.

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“…qRT-PCR and qPCR were used to measure MHV68 viral gene expression and genome copy, respectively, as previously described [65]. Total RNA was isolated from the treated cells using TRIzol reagent (Invitrogen) as described in the manufacturer's instructions.…”

Section: Qrt-pcr Qpcr and Western Blotmentioning

confidence: 99%

“…Total RNA was isolated from the treated cells using TRIzol reagent (Invitrogen) as described in the manufacturer's instructions. qRT-PCR was carried out with the specific primers corresponding to MHV68 ORF73, ORF50, ORF59, and ORF25 [65]. To measure MHV68 genome copy, genomic DNA was isolated with a Tianamp Genomic DNA kit (DP304-02; TianGen) and used for qPCR with the primers corresponding to ORF50.…”

Section: Qrt-pcr Qpcr and Western Blotmentioning

confidence: 99%

Interleukin 16 contributes to gammaherpesvirus pathogenesis by inhibiting viral reactivation

Liu

Lei

et al. 2020

PLoS Pathog

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Gammaherpesviruses have evolved various strategies to take advantage of host cellular factors or signaling pathways to establish a lifelong latent infection. Like the human gammaherpesvirus Epstein-Barr virus, murine gammaherpesvirus 68 (MHV68) establishes and maintains latency in the memory B cells during infection of laboratory mice. We have previously shown that MHV68 can immortalize fetal liver-derived B cells that induce lymphomas when injected into immunodeficient mice. Here we identify interleukin 16 (IL16) as a most abundantly expressed cytokine in MHV68-immortalized B cells and show that MHV68 infection elevates IL16 expression. IL16 is not important for MHV68 lytic infection but plays a critical role in MHV68 reactivation from latency. IL16 deficiency increases MHV68 lytic gene expression in MHV68-immortalized B cells and enhances reactivation from splenic latency. Correlatively, IL16 deficiency increases the frequency of MHV68-infected plasma cells that can be attributed to enhanced MHV68 reactivation. Furthermore, similar to TPA-mediated lytic replication of Kaposi's sarcoma-associated herpesvirus, IL16 deficiency markedly induces Tyr705 STAT3 de-phosphorylation and elevates p21 expression, which can be counteracted by the tyrosine phosphatase inhibitor orthovanadate. Importantly, orthovanadate strongly blocks MHV68 lytic gene expression mediated by IL16 deficiency. These data demonstrate that virus-induced IL16 does not directly participate in MHV68 lytic replication, but rather inhibits virus reactivation to facilitate latent infection, in part through the STAT3-p21 axis.

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Regulation of gammaherpesvirus lytic replication by endoplasmic reticulum stress–induced transcription factors ATF4 and CHOP

Cited by 15 publications

References 53 publications

Rosiglitazone inhibits PM2.5-induced cytotoxicity in human lung epithelial A549 cells

Rosiglitazone inhibits PM2.5-induced cytotoxicity in human lung epithelial A549 cells

A Human Gain-of-Function STING Mutation Causes Immunodeficiency and Gammaherpesvirus-Induced Pulmonary Fibrosis in Mice

Interleukin 16 contributes to gammaherpesvirus pathogenesis by inhibiting viral reactivation

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