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Review
. 2021 Jan 11:11:624556.
doi: 10.3389/fimmu.2020.624556. eCollection 2020.

Function and Regulation of Nuclear DNA Sensors During Viral Infection and Tumorigenesis

Fan Zhang  1   2 , Yi Yuan  1   2   3 , Feng Ma  1   2
Affiliations
Review

Function and Regulation of Nuclear DNA Sensors During Viral Infection and Tumorigenesis

Fan Zhang et al. Front Immunol. .

Abstract

IFI16, hnRNPA2B1, and nuclear cGAS are nuclear-located DNA sensors that play important roles in initiating host antiviral immunity and modulating tumorigenesis. IFI16 triggers innate antiviral immunity, inflammasome, and suppresses tumorigenesis by recognizing double-stranded DNA (dsDNA), single-stranded DNA (ssDNA), damaged nuclear DNA, or cooperatively interacting with multiple tumor suppressors such as p53 and BRCA1. hnRNPA2B1 initiates interferon (IFN)-α/β production and enhances STING-dependent cytosolic antiviral signaling by directly binding viral dsDNA from invaded viruses and facilitating N6 -methyladenosine (m6A) modification of cGAS, IFI16, and STING mRNAs. Nuclear cGAS is recruited to double-stranded breaks (DSBs), suppresses DNA repair, and promotes tumorigenesis. This review briefly describes the nuclear functions of IFI16, hnRNPA2B1, and cGAS, and summarizes the transcriptional, post-transcriptional, and post-translational regulation of these nuclear DNA sensors.

Keywords: IFI16; cGAS; hnRNPA2B1; nuclear DNA sensor; p53; tumorigenesis; type I interferon.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Major functions of nuclear DNA sensors. Upon detecting nuclear viral DNA, IFI16 is transported to the cytoplasm to activate the STING signaling cascade, inducing IFN‐Is expression through the TBK1‐IRF3 and NF‐κB axis. IFI16 also activates inflammasome to promote IL-1β and IL-18 maturation. Additionally, IFI16 functions as a transcriptional repressor to restrict viral replication by associating with transcription factors or promoters, preventing transcription factors from binding to promoters, and inducing chromatin marker changes. Nuclear hnRNPA2B1 dimerizes and is demethylated by JMJD6 after binding to viral dsDNA, resulting in the cytoplasmic translocation of hnRNPA2B1. The cytoplasmic hnRNPA2B1 activates the STING-TBK1-IRF3 signal to facilitate the transcription of IFN-Is. Moreover, demethylated hnRNPA2B1 enhances nucleocytoplasmic trafficking and translates cGAS, STING, and IFI16 mRNAs to amplify the antiviral immune response. Besides, the roles of nuclear DNA sensors during tumorigenesis have also been investigated. IFI16 is shown to act as a tumor suppressor in several types of cancers by interacting with p53 and enhancing p53-mediated transcriptional activation. In turn, functional activation of p53 stimulate the transcription of IFI16 through associating with the regulatory region of the IFI16 promoter. DNA damage triggers nuclear translocation of cGAS. Nuclear cGAS promotes tumorigenesis by modulating the DNA damage response and increasing genomic instability. ASC, apoptosis-associated speck-like protein containing a CARD; STING, stimulator of interferon genes; TBK1, TANK-binding kinase 1; IKK, IκB kinase; IRF3, interferon regulatory factor 3; IFN-I, type I interferon; A2B1, hnRNPA2B1; JMJD6, jumonji domain containing 6; Me, methylation; m6A, N6-Methyladenosine; FTO, fat mass and obesity-associated protein; KPNA, karyopherin alpha; PARP1, Poly (ADP-Ribose) Polymerase 1. γH2AX, phosphorylated H2A histone family member X (H2AX) on serine 139.
Figure 2
Figure 2
Regulation of nuclear DNA sensors. The expression and activation of DNA sensors are finely controlled during viral infection and tumorigenesis. p53 facilitates IFI16 transcription by directly binding to the promoter region of IFI16, and IL-6 drives IFI16 transcription in a STAT3-dependent manner. Post-transcriptional regulation also involves modulating the expression of nuclear DNA sensors. During DNA virus infection, hnRNPA2B1 functions as an m6A modulator to promote nucleocytoplasmic trafficking of cGAS and IFI16 mRNAs. UL41 from HSV-1 significantly reduces the expression of cGAS and IFI16 by degrading their transcripts. Furthermore, PTMs, particularly the phosphorylation, ubiquitination, acetylation, and methylation, play critical roles in regulating the activity and stability of nuclear DNA sensors. Phosphorylation of IFI16 controls its subcellular localization, and related antiviral immunity and BLK-mediated phosphorylation of cGAS facilitates its cytosolic retention. ICP0 from HSV-1 induces the ubiquitination and proteasome-dependent degradation of IFI16 and thus suppresses inflammasome activation. STING promotes IFI16 degradation via the ubiquitin-proteasome system by TRIM21. The acetyltransferase p300 mediates acetylation of IFI16 during HSV-1 infection, an essential step for inflammasome assembly and cytoplasmic translocation, activation of cytoplasmic STING signaling, and downstream IFN-β production. The sensing ability of IFI16 is modulated by acetylation of Lys99 and Lys128 within its NLS, and this PTM of IFI16 promotes the cytoplasmic translocation of IFI16, whereas HDACs promotes its nuclear import. hnRNPA2B1 is demethylated by JMJD6 in the HSV-1-infected cells, which consequently initiates IFN-α/β production and enhances STING-dependent cytoplasmic antiviral signaling. BLK, B-lymphoid tyrosine kinase; MVB, multivesicular bodies; ICP0, human HSV-1 infected cell polypeptide 0; TRIM21, tripartite motif-containing protein 21; Ub, Ubiquitination; Ac, Acetylation; Me, Methylation; STAT3, signal transducer and activator of transcription 3; NLS, nuclear localization signal; HDAC, histone deacetylase; PRMT5, protein arginine N-methyltransferase 5.
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