Suppression of the antiviral response by an influenza histone mimic

Abstract

Viral infection is commonly associated with virus-driven hijacking of host proteins. Here we describe a novel mechanism by which influenza virus affects host cells through the interaction of influenza non-structural protein 1 (NS1) with the infected cell epigenome. We show that the NS1 protein of influenza A H3N2 subtype possesses a histone-like sequence (histone mimic) that is used by the virus to target the human PAF1 transcription elongation complex (hPAF1C). We demonstrate that binding of NS1 to hPAF1C depends on the NS1 histone mimic and results in suppression of hPAF1C-mediated transcriptional elongation. Furthermore, human PAF1 has a crucial role in the antiviral response. Loss of hPAF1C binding by NS1 attenuates influenza infection, whereas hPAF1C deficiency reduces antiviral gene expression and renders cells more susceptible to viruses. We propose that the histone mimic in NS1 enables the influenza virus to affect inducible gene expression selectively, thus contributing to suppression of the antiviral response.

Targeting Cell Division Cycle 25 Homolog B To Regulate Influenza Virus Replication

“…5B). This finding is in agreement with previous findings that NS1 is chromatin bound to prevent transcription elongation of antiviral genes and that vRNP is found associated with cellular chromatin (37,55). In contrast, NS1 and NP proteins are not found in the chromatin fraction of infected cells treated with NSC95397.…”

“…In addition to its known role in the cytoplasm to inhibit RLR signaling, a pool of influenza NS1 protein is also found in the nucleus of infected cells which is thought to modulate transcription of the host's antiviral genes (17,51,52). Nuclear NS1 has been shown to inhibit transcription elongation in addition to maturation and export of host mRNA (28,37,53). Additionally, a report has previously shown that IAV expressing nonphosphorylated NS1 protein is attenuated in vitro, displaying slower growth, smaller plaque size, and delayed localization into discrete intranuclear foci (38).…”

“…NS1 also has been implicated in inhibition of host mRNA maturation and nuclear export and promotion of translation of viral mRNA (28,29,31,35,36). A recent study also demonstrated strain-specific NS1 targeting to host chromatin, specifically, to transcriptionally active loci (e.g., viral inducible gene), by mimicking the histone tail to block active host transcription elongation (37). NS1 protein is shuttled between cytoplasmic and nuclear compartments throughout infection to facilitate these actions (17).…”

SUMOylation Affects the Interferon Blocking Activity of the Influenza A Nonstructural Protein NS1 without Affecting Its Stability or Cellular Localization

“…Out of the 10 to 11 viral proteins encoded by influenza A virus, one of the most functionally diverse is the nonstructural viral protein NS1, which has been associated with numerous roles during influenza infection, including the modulation of viral RNA (vRNA) replication (3)(4)(5)(6), general inhibition of the nuclear export of mRNAs carrying polyadenylated tails (7,8), inhibition of the transcriptional elongation of host genes (9), regulation of host and viral protein synthesis (recently reviewed by Yanguez and Nieto [10]), and the neutralization of the activity of some of the interferon (IFN)-induced antiviral proteins, such as 2=,5=-oligoadenylate synthetase (OAS)/RNase L (11) and the double-stranded RNA (dsRNA)-dependent protein kinase R (PKR) (12)(13)(14)(15)(16)(17)(18). However, the main function attributed to NS1 is the neutralization of the initial signaling pathway leading to the production of type I IFN (reviewed by Krug et al and Hale et al [19,20]).…”

Effects of the Paf1 Complex and Histone Modifications on snoRNA 3′-End Formation Reveal Broad and Locus-Specific Regulation

“…The Paf1C in higher eukaryotes also has gene-specific functions, such as regulating the expression of genes dependent on the Wnt, Notch, and Hedgehog signaling pathways (31)(32)(33)(34). These many roles may explain why perturbations of Paf1C in higher eukaryotes can alter stem cell pluripotency, development, antiviral responses, and cancer progression (31,32,(34)(35)(36)(37)(38)(39)(40).…”