HIV-2/SIV Vpx targets a novel functional domain of STING to selectively inhibit cGAS–STING-mediated NF-κB signalling

Su, Jiaming; Rui, Yajuan; Lou, Meng; Yin, Lu; Xiong, Hanchu; Zhou, Zhenbang; Shen, Si; Chen, Ting; Zhengguo, Zhang; Zhao, Na; Zhang, Wei; Cai, Yong; Markham, Richard B.; Zheng, Shu; Xu, Rongzhen; Wei, Wei; Yu, Xiaofang

doi:10.1038/s41564-019-0585-4

Cited by 46 publications

(48 citation statements)

References 67 publications

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“…Vpr insensitivity of NF-ĸB-independent ubiquitin and EF1α promoters ( Figure 6) is consistent with this model, summarized in Figure 7 figure supplement 1A. This is important because inhibition of transfected plasmid driven protein expression may explain the effect of cotransfected SIV Vpr on STING and cGAS signaling reported recently (Su et al, 2019). Note that STING expression was not affected by Vpr co-expression but STING was expressed from the Vpr and NF-ĸB-insensitive EF1α promoter ( Figure 6), whereas cGAS, which was not measured by western blot, was expressed from a Vpr and NF-ĸB-sensitive ( Figure 6) CMV driven plasmid VR1012 (Hartikka et al, 1996).…”

Section: Discussionsupporting

confidence: 85%

HIV-1 Vpr antagonizes innate immune activation by targeting karyopherin-mediated NF-κB/IRF3 nuclear transport

Khan

Sumner

Rasaiyaah

et al. 2020

eLife

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HIV-1 must replicate in cells that are equipped to defend themselves from infection through intracellular innate immune systems. HIV-1 evades innate immune sensing through encapsidated DNA synthesis and encodes accessory genes that antagonize specific antiviral effectors. Here, we show that both particle associated, and expressed HIV-1 Vpr, antagonize the stimulatory effect of a variety of pathogen associated molecular patterns by inhibiting IRF3 and NF-κB nuclear transport. Phosphorylation of IRF3 at S396, but not S386, was also inhibited. We propose that, rather than promoting HIV-1 nuclear import, Vpr interacts with karyopherins to disturb their import of IRF3 and NF-κB to promote replication in macrophages. Concordantly, we demonstrate Vpr-dependent rescue of HIV-1 replication in human macrophages from inhibition by cGAMP, the product of activated cGAS. We propose a model that unifies Vpr manipulation of nuclear import and inhibition of innate immune activation to promote HIV-1 replication and transmission.

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Section: Discussionsupporting

confidence: 85%

HIV-1 Vpr antagonizes innate immune activation by targeting karyopherin-mediated NF-κB/IRF3 nuclear transport

Khan

Sumner

Rasaiyaah

et al. 2020

eLife

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“…These findings extend recent observations that Vpx binds STING to suppress NF-B activation downstream of DNA sensing (28). This preceding study did not explore the role of Vpx as an NF-B signalling antagonist in the setting of cognate virus infection in the absence of pharmacological STING activation or test Vpx NF-B antagonism against the full range of NF-B agonists (28). However, similar to this work, we also found that Vpx did not inhibit cGAS/STING-induced IRF3 activation (Supplementary Fig1 E-G).…”

Section: Vpx Blocks P65 Nuclear Translocationsupporting

confidence: 90%

“…A mutant of Vpx that was recently described to prevent interaction with STING (R51AS52A) also still antagonised gene expression activated by p65 expression in a dosedependent manner as effectively as wild-type Vpx (Fig 3C). This was also true for Vpx Q76R, which is deficient for DCAF1 binding, suggesting DCAF1 independence for this activity (Fig3D) (22,27,28). Concordantly, Vpx inhibited NF-B activation in HEK293T cells depleted of DCAF1 by siRNA (Figs 3E, F).…”

Section: Vpx Inhibition Is Independent Of Dcaf1 Samhd1 and Hushsupporting

confidence: 57%

HIV-2/SIV Vpx antagonises NF-κB activation by targeting p65

Cai

Whelan

et al. 2021

Preprint

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The NF-𝜅B family of transcription factors and associated signalling pathways are abundant and ubiquitous in human immune responses. Activation of NF-𝜅B transcription factors by viral pathogen-associated molecular patterns, such as viral RNA and DNA, is fundamental to anti-viral innate immune defences and pro-inflammatory cytokine production that steers adaptive immune responses. Diverse non-viral stimuli, such as lipopolysaccharide and cytokines, also activate NF-𝜅B and the same anti-pathogen gene networks. Viruses adapted to human cells often encode multiple proteins aimed at varied NF-𝜅B pathway targeted to mitigate the anti-viral effects of NF-𝜅B-dependent host immunity. In this study we have demonstrated using numerous assays, in a number of different cell types, that plasmid-encoded or virus-delivered Simian Immunodeficiency Virus (SIV) accessory protein Vpx is a broad antagonist of NF-𝜅B signalling active against diverse innate NF-𝜅B agonists. Using targeted Vpx mutagenesis, we showed that this novel Vpx phenotype is independent of known Vpx cofactor DCAF1 and other cellular binding partners, including SAMHD1, STING and the HUSH complex. We found that Vpx co-immunoprecipitated with canonical NF-𝜅B transcription factor p65 and not NF-𝜅B transcription factor proteins p50 or p100, preventing nuclear translocation of p65, a novel mechanism of NF-𝜅B antagonism by lentiviruses. We found that broad antagonism of NF-𝜅B activation by Vpx was conserved across distantly related lentiviruses as well as for Vpr from SIV Mona monkey (SIVmon), which has Vpx-like SAMHD1-degradation activity.

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“…Thus, inhibition of NF-κB nuclear transport by Vpr likely explains the observation that Vpr suppresses expression from the CMV MIEP, but not promoters that are independent of NF-κB activity for expression. This is important because previous studies have used Vpr co-transfection with CMV MIEP driven promoters to address Vpr function (Su et al, 2019).…”

Section: Vpr Inhibits Nf-κb P65 Nuclear Translocation and Nf-κb Sensimentioning

confidence: 99%

“…Vpr insensitivity of NF-ĸB-independent ubiquitin and EF1α promoters ( Figure 6) is consistent with this model, summarized in Figure S7. This is important because inhibition of transfected plasmid driven protein expression may explain the effect of cotransfected SIV Vpr on STING and cGAS signaling reported recently (Su et al, 2019). Note that STING expression was not affected by Vpr co-expression but STING was expressed from the Vpr and NF-ĸB-insensitive EF1α promoter (Figure 6), whereas cGAS, which was not measured by western blot, was expressed from a Vpr and NF-ĸB-sensitive ( Figure 6) CMV driven plasmid VR1012 (Hartikka et al, 1996).…”

mentioning

confidence: 99%

HIV-1 Vpr antagonizes innate immune activation by targeting karyopherin-mediated NF-κB/IRF3 nuclear transport

Khan

Sumner

Rasaiyaah

et al. 2020

Preprint

View full text Add to dashboard Cite

AbstractHIV-1 must replicate in cells that are equipped to defend themselves from infection through intracellular innate immune systems. HIV-1 evades innate immune sensing through encapsidated DNA synthesis and encodes accessory genes that antagonize specific antiviral effectors. Here we show that both particle associated, and expressed HIV-1 Vpr, antagonize the stimulatory effect of a variety of pathogen associated molecular patterns by inhibiting IRF3 and NF-κB nuclear transport. Phosphorylation of IRF3 at S396, but not S386, was also inhibited. We propose that, rather than promoting HIV-1 nuclear import, Vpr interacts with karyopherins to disturb their import of IRF3 and NF-κB to promote replication in macrophages. Concordantly, we demonstrate Vpr dependent rescue of HIV-1 replication in human macrophages from inhibition by cGAMP, the product of activated cGAS. We propose a model that unifies Vpr manipulation of nuclear import and inhibition of innate immune activation to promote HIV-1 replication and transmission.

show abstract

HIV-2/SIV Vpx targets a novel functional domain of STING to selectively inhibit cGAS–STING-mediated NF-κB signalling

Cited by 46 publications

References 67 publications

HIV-1 Vpr antagonizes innate immune activation by targeting karyopherin-mediated NF-κB/IRF3 nuclear transport

HIV-1 Vpr antagonizes innate immune activation by targeting karyopherin-mediated NF-κB/IRF3 nuclear transport

HIV-2/SIV Vpx antagonises NF-κB activation by targeting p65

HIV-1 Vpr antagonizes innate immune activation by targeting karyopherin-mediated NF-κB/IRF3 nuclear transport

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