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Interrogating Host Antiviral Environments Driven by Nuclear DNA Sensing: a Multiomic Perspective

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Interrogating Host Antiviral Environments Driven by Nuclear DNA Sensing: a Multiomic Perspective biomolecules Review Interrogating Host Antiviral Environments Driven by Nuclear DNA Sensing: A Multiomic Perspective Timothy R. Howard and Ileana M. Cristea * Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-609-258-9417 Received: 12 November 2020; Accepted: 23 November 2020; Published: 24 November 2020 Abstract: Nuclear DNA sensors are critical components of the mammalian innate immune system, recognizing the presence of pathogens and initiating immune signaling. These proteins act in the nuclei of infected cells by binding to foreign DNA, such as the viral genomes of nuclear-replicating DNA viruses herpes simplex virus type 1 (HSV-1) and human cytomegalovirus (HCMV). Upon binding to pathogenic DNA, the nuclear DNA sensors were shown to initiate antiviral cytokines, as well as to suppress viral gene expression. These host defense responses involve complex signaling processes that, through protein–protein interactions (PPIs) and post-translational modifications (PTMs), drive extensive remodeling of the cellular transcriptome, proteome, and secretome to generate an antiviral environment. As such, a holistic understanding of these changes is required to understand the mechanisms through which nuclear DNA sensors act. The advent of omics techniques has revolutionized the speed and scale at which biological research is conducted and has been used to make great strides in uncovering the molecular underpinnings of DNA sensing. Here, we review the contribution of proteomics approaches to characterizing nuclear DNA sensors via the discovery of functional PPIs and PTMs, as well as proteome and secretome changes that define a host antiviral environment. We also highlight the value of and future need for integrative multiomic efforts to gain a systems-level understanding of DNA sensors and their influence on epigenetic and transcriptomic alterations during infection. Keywords: DNA sensing; IFI16; cGAS; innate immunity; protein interactions; virus–host interactions; post-translational modifications; mass spectrometry; proteomics; transcriptomics 1. Introduction Eukaryotic cells are relentlessly assailed by a myriad of pathogens, thereby needing to constantly evolve and expand their mechanisms for pathogen detection and host defense. During infection, pathogens bring foreign sugars, lipids, proteins, and nucleic acids into host cells. These foreign molecules can act as pathogen-associated molecular patterns (PAMPs), and the ability of the cell to detect them is critical for the initiation of host defense mechanisms and the inhibition of virus production and spread. Thus, cells utilize specialized proteins known as pattern-recognition receptors (PRRs) to detect PAMPs [1]. A common PAMP detected by host cells is the pathogenic double-stranded DNA (dsDNA) from bacteria, DNA viruses, and some RNA viruses (i.e., retroviruses) [2]. PRRs for dsDNA, known as DNA sensors, bind to the pathogenic DNA and initiate defense programs that include innate immune signaling, inflammatory responses, and apoptosis. It was long believed that DNA sensors can only function outside of the nucleus, in order to avoid recognition of self-DNA and spurious activation of immune responses. However, the majority of the known human dsDNA viruses replicate within the nucleus, thereby depositing their viral genomes in the nuclei of infected cells. Examples of nuclear-replicating DNA viruses are herpesviruses, such as herpes simplex virus type 1 (HSV-1), Biomolecules 2020, 10, 1591; doi:10.3390/biom10121591 www.mdpi.com/journal/biomolecules Biomolecules 2020, 10, 1591 2 of 23 human cytomegalovirus (HCMV), and Kaposi’s sarcoma-associated herpesvirus (KSHV). Herpesviruses are ancient viruses that arose hundreds of millions of years ago, having ample time to co-diverge with their hosts [3–5]. The co-evolution and co-adaptation of viruses with hosts are evidenced by the diversification of PRRs and their ligand-recognition abilities [6]. Indeed, research during the past decade has demonstrated the existence of PRRs that function in nuclear sensing of pathogenic DNA [7,8]. To date, four proteins have been shown to have the ability to perform nuclear DNA sensing—in chronological order of discovery of nuclear function: interferon-inducible protein 16 (IFI16 [9–11]), interferon-inducible protein X (IFIX [12]), cyclic GMP-AMP synthase (cGAS [13–16]), and heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1 [17]). The structures of these four proteins and their currently understood mechanisms for induction of antiviral responses are illustrated in Figure1. Each nuclear DNA sensor was shown to help to induce ifnβ expression, which in turn activates numerous critical antiviral signaling pathways in adjacent cells that aim to slow the spread of infection. Ifnβ expression is thought to rely primarily on a signaling axis involving the endoplasmic reticulum membrane protein stimulator of interferon genes (STING), although STING-independent signaling has also been proposed [18]. Activation of STING leads to the phosphorylation of TANK binding kinase 1 (TBK1), which in turn phosphorylates the interferon regulatory factor 3 (IRF3). IRF3 then dimerizes, shuttles into the nucleus, and binds to the interferon-stimulated response element upstream of ifnβ to transcriptionally activate the expression of antiviral cytokines [19–22]. IFI16 was discovered as a sensor ten years ago [9], becoming the first known nuclear DNA sensor. Both IFI16 and IFIX belong to the PYHIN family of proteins [12]. These DNA sensors consist of an N-terminal pyrin domain (PYD) [23] and either one (IFIX) or two (IFI16) C-terminal HIN-200 domains [24,25] (Figure1A). The HIN-200 domains facilitate sequence-independent binding of the sensor to the viral DNA [25], while the PYD mediates homotypic oligomerization [26,27]. IFI16 was shown to bind incoming viral dsDNA at the nuclear periphery, immediately following the docking of the virus capsid at the nuclear pore, and the PYD was found to be necessary for the IFI16 recruitment to the nuclear periphery [15]. The IFI16 oligomerization upon binding to viral DNA and recruitment of other host factors is thought to build an antiviral scaffold capable of both activating immune signaling [9,10,26,28,29] and suppressing viral transcription [29–32] (Figure1B). A subset of IFI16 was shown to be able to shuttle between the nucleus and the cytoplasm to function in DNA sensing in a localization-dependent manner [9,10]. However, during the early stages of infection with nuclear-replicating viruses, IFI16 does not appear to move to the cytoplasm, remaining predominantly nuclear. Thus, a still unanswered question is how IFI16 communicates with STING or whether a STING-independent mechanism also contributes to ifnβ induction. IFIX was also shown to bind dsDNA in a sequence-independent manner and to help induce antiviral cytokine expression upon herpesvirus infection [12]. Furthermore, similar to IFI16, this PYHIN protein displayed pronounced ability to undergo nuclear oligomerization via its PYD [26] and was shown to also function in suppressing viral gene expression [33]. However, very few studies have so far focused on IFIX during infection, and the mechanisms involved in IFIX-mediated antiviral responses remain poorly understood. The mechanism by which cytoplasmic cGAS induces STING activation is well defined. cGAS contains an NTase core domain (Figure1A) that catalyzes the formation of 2 030-cyclic GMP-AMP (cGAMP) (Figure1B). After binding to dsDNA, cGAS dimerizes and initiates cGAMP production. This small molecule then binds to STING, causing a conformational change and dimerization that leads to TBK1 phosphorylation. The additional presence of cGAS in the nucleus has been initially the subject of debate, although it was shown to form a functional nuclear interaction with IFI16 [14]. However, in recent years, it has become accepted that cGAS indeed has nuclear localization in different cell types, and studies have characterized mechanisms that prevent its autoreactivity [34] or that underlie its nuclear function in inhibiting DNA damage repair [16,35]. Biomolecules 2020, 10, x 2 of 24 associated herpesvirus (KSHV). Herpesviruses are ancient viruses that arose hundreds of millions of years ago, having ample time to co-diverge with their hosts [3–5]. The co-evolution and co-adaptation of viruses with hosts are evidenced by the diversification of PRRs and their ligand-recognition abilities [6]. Indeed, research during the past decade has demonstrated the existence of PRRs that function in nuclear sensing of pathogenic DNA [7,8]. To date, four proteins have been shown to have the ability to perform nuclear DNA sensing—in chronological order of discovery of nuclear function: interferon-inducible protein 16 (IFI16 [9–11]), interferon-inducible protein X (IFIX [12]), cyclic GMP-AMP synthase (cGAS [13–16]), and heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1 [17]). The structures of these four proteins and their currently understood mechanisms for induction of antiviral responses are Biomoleculesillustrated2020, in10 ,Figure 1591 1. Each nuclear DNA sensor was shown to help to induce ifnβ expression, which 3 of 23 in turn activates numerous critical antiviral signaling pathways in adjacent cells that aim to slow the spread of infection. Ifnβ expression is thought to rely primarily on a signaling axis involving the Finally, the most recently discovered nuclear DNA sensor,
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