Herpes Simplex Virus 1 Abrogates the cGAS/STING-Mediated Cytosolic DNA-Sensing Pathway via Its Virion Host Shutoff Protein, UL41

Abstract

Cyclic GMP-AMP synthase (cGAS) is a key DNA sensor capable of detecting microbial DNA and activating the adaptor protein stimulator of interferon genes (STING), leading to interferon (IFN) production and host antiviral responses. Cells exhibited reduced type I IFN production in response to cytosolic DNA in the absence of cGAS. Although the cGAS/STING-mediated DNA-sensing signal is crucial for host defense against many viruses, especially for DNA viruses, few viral components have been identified to specifically target this signaling pathway. Herpes simplex virus 1 (HSV-1) is a DNA virus that has evolved multiple strategies to evade host immune responses. In the present study, we found that HSV-1 tegument protein UL41 was involved in counteracting the cGAS/STING-mediated DNA-sensing pathway. Our results showed that wild-type (WT) HSV-1 infection could inhibit immunostimulatory DNA-induced activation of the IFN signaling pathway compared with the UL41-null mutant virus (R2621), and ectopic expression of UL41 decreased cGAS/STINGmediated IFN-␤ promoter activation and IFN-␤ production. Further study indicated that UL41 reduced the accumulation of cGAS to abrogate host recognition of viral DNA. In addition, stable knockdown of cGAS facilitated the replication of R2621 but not WT HSV-1. For the first time, HSV-1 UL41 was demonstrated to evade the cGAS/ STING-mediated DNA-sensing pathway by degrading cGAS via its RNase activity.IMPORTANCE HSV-1 is well known for its ability to evade host antiviral responses and establish a lifelong latent infection while triggering reactivation and lytic infection under stress. Currently, whether HSV-1 evades the cytosolic DNA sensing and signaling is still poorly understood. In the present study, we found that tegument protein UL41 targeted the cGAS/STING-mediated cellular DNA-sensing pathway by selectively degrading cGAS mRNA. Knockdown of endogenous cGAS could facilitate the replication of R2621 but not WT HSV-1. Furthermore, UL41 was shown for the first time to act directly on cGAS. Findings in this study could provide new insights into the host-virus interaction and help develop new approaches against HSV-1.KEYWORDS HSV-1, vhs/UL41, cGAS, DNA sensing T he innate immune system is the first line of defense against invading pathogens and is crucial for the subsequent activation of the adaptive immune response. The first step in innate immunity is to detect the invading pathogen through various pathogen recognition receptors (PRRs) which recognize pathogen-associated molecular patterns and trigger the production of type I interferon (IFN) and other antiviral factors (1, 2). Besides Toll-like receptors in the cellular membrane or endosome, Nod-like receptors and the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) in the cytoplasm, there are also several recently discovered cytosolic DNA sensors, such as cyclic GMP-AMP (cGAMP) synthase (cGAS), gamma interferon-inducible protein 16

HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection

“…Like most DNA viruses, HSV1 has evolved multiple mechanisms to evade induction of type I IFN (Christensen and Paludan, 2017). This includes close to 10 known mechanisms, several of which specifically target the cGAS-STING pathway (Christensen et al, 2016;Deschamps and Kalamvoki, 2017;Huang et al, 2018;Su and Zheng, 2017;Ye et al, 2017;Zhang et al, 2018), and some inhibit more than one pathway by targeting proteins used by multiple pathways (Lin et al, 2004;Ma et al, 2012;Orzalli et al, 2012a;Wang et al, 2013b). HSV1 also inhibits autophagy through ICP34.5, and this contributes to the neuropathology of the virus (Orvedahl et al, 2007).…”

“…This indicates that both the TLR3-TRIF and cGAS-STING pathways are involved in control of HSV1 infections. In further support of a role for the cGAS-STING pathway in control of HSV1, there are now reports of close to 10 HSV1-encoded proteins targeting this pathway (Christensen et al, 2016;Deschamps and Kalamvoki, 2017;Huang et al, 2018;Orzalli et al, 2012b;Su and Zheng, 2017;Verpooten et al, 2009;Wang et al, 2013b;Ye et al, 2017;Zhang et al, 2018). However, it remains unresolved how HSV1 evades the IFN-mediated immune response in the brain.…”

The herpesviral antagonist m152 reveals differential activation of STING ‐dependent IRF and NF ‐κB signaling and STING 's dual role during MCMV infection

“…While some herpesviral antagonists target cGAS directly Zhang et al, 2016;Su & Zheng, 2017), others mediate the degradation of STING (Kim et al, 2017) or target downstream signaling pathways (Christensen et al, 2016). While some herpesviral antagonists target cGAS directly Zhang et al, 2016;Su & Zheng, 2017), others mediate the degradation of STING (Kim et al, 2017) or target downstream signaling pathways (Christensen et al, 2016).…”

“…The cGAS-STING signaling pathway plays a pivotal role in the antiviral innate immune response with the number of corresponding viral antagonists rising steadily. While some herpesviral antagonists target cGAS directly Zhang et al, 2016;Su & Zheng, 2017), others mediate the degradation of STING (Kim et al, 2017) or target downstream signaling pathways (Christensen et al, 2016). However, the m152 protein is a clear stand out: It modulates this pathway differentially by antagonizing cGAS-STING-mediated activation of type I IFN signaling, while leaving cGAS-STING-mediated activation of NF-jB signaling intact, and it does so by delaying trafficking of STING from the ER to the Golgi compartment (Fig 9).…”

The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders

“…Through a variety of mechanisms, several DNA viruses such as adenovirus, herpes simplex virus (HSV)-1, and human papilloma virus (HPV) have been shown to induce or actively inhibit a STING-dependent type I IFN response (Anghelina et al, 2016; Ishikawa et al, 2009; Lam and Falck-Pedersen, 2014; Lam et al, 2014; Liang et al, 2015; Sunthamala et al, 2014). For example, over a dozen proteins of HSV-1 have been found to actively suppress cytosolic-DNA recognition by the cGAS/STING pathway (Christensen et al, 2016; Horan et al, 2013; Ishikawa et al, 2009; Kalamvoki and Roizman, 2014; Su and Zheng, 2017; Xu et al, 2017; Ye et al, 2017; Zhang et al, 2016; Zheng, 2018). Similarly, the E2 proteins of HPV16 inhibit the transcription of different ISGs by targeting STING (Sunthamala et al, 2014).…”