The ER-Associated Protein ZDHHC1 Is a Positive Regulator of DNA Virus-Triggered, MITA/STING-Dependent Innate Immune Signaling

Zhou, Qian; Lin, Heng; Wang, Suyun; Wang, Shuai; Ran, Yong; Liu, Ying; Ye, Wen; Xiong, Xiaozhe; Zhong, Bo; Shu, Hong; Wang, Yanyi

doi:10.1016/j.chom.2014.09.006

Cited by 133 publications

(134 citation statements)

References 40 publications

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“…Many host cell factors have been reported to regulate HSV-1 replication and/or pathogenicity in the CNS, as determined using experiments performed in genetically modified mice (33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47). Notably, most of the host cell factors identified were regulators of innate and/or acquired immunity (33)(34)(35)(36)(37)(39)(40)(41)(42)(43)(44)(45)(46)(47).…”

Section: G and I) In Addition Increased Levels Of Neutrophil-likmentioning

confidence: 99%

p53 Is a Host Cell Regulator during Herpes Simplex Encephalitis

Maruzuru

Koyanagi

Takemura

et al. 2016

J Virol

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ABSTRACTp53 is a critical host cell factor in the cellular response to a broad range of stress factors. We recently reported that p53 is required for efficient herpes simplex virus 1 (HSV-1) replication in cell culture. However, a defined role for p53 in HSV-1 replication and pathogenesis in vivo remains elusive. In this study, we examined the effects of p53 on HSV-1 infection in vivo using p53-deficient mice. Following intracranial inoculation, p53 knockout reduced viral replication in the brains of mice and led to significantly reduced rates of mortality due to herpes simplex encephalitis. These results suggest that p53 is an important host cell regulator of HSV-1 replication and pathogenesis in the central nervous system (CNS). IMPORTANCEHSV-1 causes sporadic cases of encephalitis, which, even with antiviral therapy, can result in severe neurological defects and even death. Many host cell factors involved in the regulation of CNS HSV-1 infection have been investigated using genetically modified mice. However, most of these factors are immunological regulators and act via immunological pathways in order to restrict CNS HSV-1 infection. They therefore provide limited information on intrinsic host cell regulators that may be involved in the facilitation of CNS HSV-1 infection. Here we demonstrate that a host cell protein, p53, which has generally been considered a host cell restriction factor for various viral infections, is required for efficient HSV-1 replication and pathogenesis in the CNS of mice. This is the first report showing that p53 positively regulates viral replication and pathogenesis in vivo and provides insights into its molecular mechanism, which may suggest novel clinical treatment options for herpes simplex encephalitis. Herpes simplex virus 1 (HSV-1) is an etiological agent in various human mucocutaneous diseases, such as herpes labialis, genital herpes, herpetic whitlow, and keratitis. HSV-1 also causes herpes simplex encephalitis (HSE), which is sporadic and which can be lethal or result in severe neurological defects in a significant fraction of survivors, even with antiviral therapy (1).p53 is a multifunctional host protein that plays a central role in cellular responses to a broad range of stress factors through its regulation of various cellular pathways, such as apoptosis, cell cycling, cellular senescence, DNA repair, autophagy, and innate immune control (2, 3). Since viral infection is a type of stress, it appears that viral infection activates p53 responses that trigger apoptosis of infected cells, thereby suppressing viral replication (4). Thus, when a person is infected with a DNA virus, viral genome replication induces host DNA damage responses (DDRs), which activate apoptotic p53 responses (4). In RNA virus infections, double-stranded RNAs are produced, and these doublestranded RNAs trigger antiviral responses mediated by type I interferon (IFN-I) signaling, in which p53 appears to function as both an upstream and a downstream regulator (5, 6). In agreement with these observation...

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Section: G and I) In Addition Increased Levels Of Neutrophil-likmentioning

confidence: 99%

p53 Is a Host Cell Regulator during Herpes Simplex Encephalitis

Maruzuru

Koyanagi

Takemura

et al. 2016

J Virol

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“…This resource is now available for further studies. Another study demonstrated that STING constitutively interacts with the ER-associated protein ZDHHC1 and that this interaction is essential for STING dimerization and the recruitment of TBK1 (58). Finally, it has been reported that a series of cysteines in the membrane-spanning regions of STING are essential for IFN-␤ induction (59).…”

Section: Recognition Of Dnamentioning

confidence: 99%

Activation and Regulation of DNA-Driven Immune Responses

Paludan

2015

Microbiol Mol Biol Rev

110

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SUMMARY The innate immune system provides early defense against infections and also plays a key role in monitoring alterations of homeostasis in the body. DNA is highly immunostimulatory, and recent advances in this field have led to the identification of the innate immune sensors responsible for the recognition of DNA as well as the downstream pathways that are activated. Moreover, information on how cells regulate DNA-driven immune responses to avoid excessive inflammation is now emerging. Finally, several reports have demonstrated how defects in DNA sensing, signaling, and regulation are associated with susceptibility to infections or inflammatory diseases in humans and model organisms. In this review, the current literature on DNA-stimulated innate immune activation is discussed, and important new questions facing this field are proposed.

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“…Gapdh was used as a reference gene. Gene-specific primer sequences were described previously (11,30). The following primers were used for qPCR analysis of mouse Trim38 mRNA: 59-TGCTGGCGCTGTTATTGGG-39 (forward) and 59-GTTCACGCAATTTTGTCATGGT-39 (reverse).…”

Section: Quantitative Real-time Pcrmentioning

confidence: 99%

TRIM38 Negatively Regulates TLR3/4-Mediated Innate Immune and Inflammatory Responses by Two Sequential and Distinct Mechanisms

Xie

Yang

et al. 2015

The Journal of Immunology

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Tripartite motif (TRIM)38 is an E3 ubiquitin ligase that was reported to regulate signaling in innate immune and inflammatory responses in certain cell lines. In this study, we show that Trim38 deficiency markedly increased TLR3- and TLR4-mediated induction of type I IFNs and proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6, in immune cells and in vivo. Trim38 deficiency also caused the mice to be more susceptible to death triggered by polyinosinic-polycytidylic acid, LPS, and Salmonella typhimurium. Mechanistically, TRIM38 catalyzed K48-linked polyubiquitination of the TLR3/4 adapter protein TIR domain–containing adapter-inducing IFN-β at K228 and promoted its proteasomal degradation in immune cells. Moreover, Trim38 was highly induced by type I IFNs, which then negatively regulated TNF-α/IL-1β signaling in IFN-β–primed immune cells, but not unprimed immune cells, by mediating degradation of Tab2 in a lysosomal-dependent process. These results suggest that Trim38 negatively regulates TLR3/4-mediated innate immune and inflammatory responses by two sequential and distinct mechanisms. This study increases our understanding of how the innate immune response is initiated during the early phase of infection to defend against microbial invasion and is efficiently terminated during the late phase to prevent excessive and harmful inflammatory responses.

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The ER-Associated Protein ZDHHC1 Is a Positive Regulator of DNA Virus-Triggered, MITA/STING-Dependent Innate Immune Signaling

Cited by 133 publications

References 40 publications

p53 Is a Host Cell Regulator during Herpes Simplex Encephalitis

p53 Is a Host Cell Regulator during Herpes Simplex Encephalitis

Activation and Regulation of DNA-Driven Immune Responses

TRIM38 Negatively Regulates TLR3/4-Mediated Innate Immune and Inflammatory Responses by Two Sequential and Distinct Mechanisms

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