Bclaf1 critically regulates the type I interferon response and is degraded by alphaherpesvirus US3

Qin, Chao; Zhang, Rui; Lang, Yue; Shao, Anwen; Xu, Aotian; Feng, Wen-hai; Han, Jun; Wang, Mengdong; He, Wanwei; Yu, Cuilian; Tang, Jun

doi:10.1371/journal.ppat.1007559

Cited by 48 publications

(59 citation statements)

References 56 publications

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“…ISGF3 translocates to the nucleus and binds to IFN-stimulated response elements (ISRE) resulting in the transcription of ISGs [ 157 , 158 , 159 , 160 ] ( Figure 3 ). Bclaf1 (bcl-2-associated transcription factor) has recently been identified as an important regulator during this process and is involved in the phosphorylation of STAT1 and STAT2 as well as facilitating the binding of ISGF3 to ISRE [ 161 ]. Impairing the function of Bclaf1 results in decreased IFNα signaling [ 161 ].…”

Section: The Interferon Response Against Hsvmentioning

confidence: 99%

“…Bclaf1 (bcl-2-associated transcription factor) has recently been identified as an important regulator during this process and is involved in the phosphorylation of STAT1 and STAT2 as well as facilitating the binding of ISGF3 to ISRE [ 161 ]. Impairing the function of Bclaf1 results in decreased IFNα signaling [ 161 ].…”

Section: The Interferon Response Against Hsvmentioning

confidence: 99%

“…pUS3 also promotes the proteasomal degradation of bclaf2 and as a result IFNα signaling and ISG induction is diminished. This was observed in HEp-2 cells infected with pUS3 null mutant HSV-1 that were unable to induce the degradation of bclaf2 compared to wild type virus [ 161 ].…”

Section: Hsv-1 Evasion Response Against the Innate Immune Systemmentioning

confidence: 99%

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Herpes Simplex Virus Type 1 Interactions with the Interferon System

Danastas

Miranda-Saksena

Cunningham

2020

IJMS

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The interferon (IFN) system is one of the first lines of defense activated against invading viral pathogens. Upon secretion, IFNs activate a signaling cascade resulting in the production of several interferon stimulated genes (ISGs), which work to limit viral replication and establish an overall anti-viral state. Herpes simplex virus type 1 is a ubiquitous human pathogen that has evolved to downregulate the IFN response and establish lifelong latent infection in sensory neurons of the host. This review will focus on the mechanisms by which the host innate immune system detects invading HSV-1 virions, the subsequent IFN response generated to limit viral infection, and the evasion strategies developed by HSV-1 to evade the immune system and establish latency in the host.

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Section: The Interferon Response Against Hsvmentioning

confidence: 99%

Section: The Interferon Response Against Hsvmentioning

confidence: 99%

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Herpes Simplex Virus Type 1 Interactions with the Interferon System

Danastas

Miranda-Saksena

Cunningham

2020

IJMS

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“…PRV UL50 can suppress type-I IFN signalling by promoting the lysosomal degradation of IFNAR1 [ 24 ]. PRV US3 impairs IFN-mediated antiviral activity by degrading Bcl-2 associated transcription factor 1 (Bclaf1), a positive regulator in IFN signalling [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

PRV UL13 inhibits cGAS–STING-mediated IFN-β production by phosphorylating IRF3

Miao

Rui

et al. 2020

Vet Res

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Cyclic GMP-AMP (cGAMP) synthase (cGAS) is an intracellular sensor of cytoplasmic viral DNA created during virus infection, which subsequently activates the stimulator of interferon gene (STING)-dependent type I interferon response to eliminate pathogens. In contrast, viruses have developed different strategies to modulate this signalling pathway. Pseudorabies virus (PRV), an alphaherpesvirus, is the causative agent of Aujeszky’s disease (AD), a notable disease that causes substantial economic loss to the swine industry globally. Previous reports have shown that PRV infection induces cGAS-dependent IFN-β production, conversely hydrolysing cGAMP, a second messenger synthesized by cGAS, and attenuates PRV-induced IRF3 activation and IFN-β secretion. However, it is not clear whether PRV open reading frames (ORFs) modulate the cGAS–STING-IRF3 pathway. Here, 50 PRV ORFs were screened, showing that PRV UL13 serine/threonine kinase blocks the cGAS–STING-IRF3-, poly(I:C)- or VSV-mediated transcriptional activation of the IFN-β gene. Importantly, it was discovered that UL13 phosphorylates IRF3, and its kinase activity is indispensable for such an inhibitory effect. Moreover, UL13 does not affect IRF3 dimerization, nuclear translocation or association with CREB-binding protein (CBP) but attenuates the binding of IRF3 to the IRF3-responsive promoter. Consistent with this, it was discovered that UL13 inhibits the expression of multiple interferon-stimulated genes (ISGs) induced by cGAS–STING or poly(I:C). Finally, it was determined that PRV infection can activate IRF3 by recruiting it to the nucleus, and PRVΔUL13 mutants enhance the transactivation level of the IFN-β gene. Taken together, the data from the present study demonstrated that PRV UL13 inhibits cGAS–STING-mediated IFN-β production by phosphorylating IRF3.

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“…PRV WT (Bartha K61), the recombinant PRV EP0-Knockout virus (PRV-EP0 KO) and KOS strain of HSV-1 were described previously (30, 31).…”

Section: Methodsmentioning

confidence: 99%

Swine Promyelocytic Leukemia Isoform II Inhibits Pseudorabies Virus Infection by Suppressing Viral Gene Transcription in PML-NBs

Yu¹,

Xu²,

Lang³

et al. 2020

Preprint

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22Promyelocytic leukaemia nuclear bodies (PML-NBs) possess an important intrinsic 23 antiviral activity against a-herpesvirus infection. PML is the structural backbone of 24 NBs, comprising different isoforms. However, the contribution of each isoform to 25 a-herpesvirus restriction is not well understood. Here, we report the role of PML-26NBs and swine PML (sPML) isoforms in pseudorabies virus (PRV) infection in its 27 natural host swine cells. We found that sPML-NBs exhibit an anti-PRV activity in 28 the context of increasing the expression level of endogenous sPML. Of four sPML 29 isoforms cloned and examined, only isoform sPML-II/IIa, not sPML-I and IVa, 30 expressed in a sPML knockout cells inhibits PRV infection. Both the unique 7b 31 region of sPML-II and sumoylation-dependent normal formation of PML-NBs are 32 required. 7b possesses a transcriptional repression activity and suppresses viral 33 gene transcription during PRV infection with the cysteine residue 589 and 599 34 being critically involved. We conclude that sPML-NBs inhibit PRV infection by 35 repressing viral gene transcription through the 7b region of sPML-II. 36 IMPORTANCE 37PML-NBs are nuclear sites that mediate the antiviral restriction of a-herpesvirus 38 gene expression and replication. However, the contrition of each PML isoform to 39 this activity of PML-NBs is not well characterized. Using PRV and its natural host 40 swine cells as a system, we have discovered that the unique C-terminus of sPML 41 isoform II is required for PML-NBs to inhibit PRV infection by directly engaging in 42 repression of viral gene transcription. Our study not only confirms in swine cells 43 that PML-NBs have an anti-viral function, but also presents a mechanism to 44 suggest that PML-NBs inhibit viral infection in an isoform specific manner. 45 MATERIALS AND METHODS 108Cell culture and viruses 109

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Bclaf1 critically regulates the type I interferon response and is degraded by alphaherpesvirus US3

Cited by 48 publications

References 56 publications

Herpes Simplex Virus Type 1 Interactions with the Interferon System

Herpes Simplex Virus Type 1 Interactions with the Interferon System

PRV UL13 inhibits cGAS–STING-mediated IFN-β production by phosphorylating IRF3

Swine Promyelocytic Leukemia Isoform II Inhibits Pseudorabies Virus Infection by Suppressing Viral Gene Transcription in PML-NBs

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