The emerging role of SARS-CoV-2 nonstructural protein 1 (nsp1) in epigenetic regulation of host gene expression

Abstract

Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes widespread changes in epigenetic modifications and chromatin architecture in the host cell. Recent evidence suggests that SARS-CoV-2 nonstructural protein 1 (nsp1) plays an important role in driving these changes. Previously thought to be primarily involved in host translation shutoff and cellular mRNA degradation, nsp1 has now been shown to be a truly multifunctional protein that affects host gene expression at multiple levels. The functions of nsp1 are surprisingly diverse and include not only the downregulation of cellular mRNA translation and stability, but also the inhibition of mRNA export from the nucleus, the suppression of host immune signaling, and, most recently, the epigenetic regulation of host gene expression. In this review, we first summarize the current knowledge on SARS-CoV-2-induced changes in epigenetic modifications and chromatin structure. We then focus on the role of nsp1 in epigenetic reprogramming, with a particular emphasis on the silencing of immune-related genes. Finally, we discuss potential molecular mechanisms underlying the epigenetic functions of nsp1 based on evidence from SARS-CoV-2 interactome studies.

Keywords: DNA polymerase alpha; H3K9me2; coronavirus; epigenetic silencing; heterochromatin; nsp1.

Figure 1.

Specific interaction between nsp1 and the catalytic subunit of DNA polymerase alpha (POLA1) may affect its epigenetic functions. (A) Domain map of POLA1 showing the nsp1-binding region and sequence motifs involved in epigenetic inheritance. Based on the diagram by Nasheuer and Onwubiko (2023). (B) The interaction between nsp1 and POLA1 may prevent regulatory proteins from accessing the flexible N-terminal region of POLA1. POLA1 is shown as a gray space-filling model. A cross-section of the catalytically inactive POLA1 exonuclease domain is shown in solid gray. The contact area between POLA1 and nsp1 is highlighted with the dashed line. Nsp1 is drawn as ribbons, with POLA1-interacting structural elements in purple and the rest in green. The dotted circle indicates a potential steric clash between nsp1 and binding partners of the flexible N-terminal region of POLA1. The schematic rendering of the nsp1-POLA1 complex is based on the published cryo-EM structure by Kilkenny et al. (2022).

Figure 2.

Nsp1 promotes transcriptional and epigenetic silencing of immune-related genes. (A) A model describing the role of nsp1 in ISG repression. Nsp1 antagonizes type I IFN signaling by inhibiting STAT1 phosphorylation in the cytoplasm. As a result, STAT1 is unable to form activated dimers with STAT2, preventing them from translocating into the nucleus and inducing ISG expression. In addition, nsp1 promotes G9a-mediated deposition of the repressive chromatin mark H3K9me2 at immune-related genomic loci through a yet unknown mechanism. The H3K9me2 mark is specifically recognized by HP1, promoting facultative heterochromatin formation. Nuclear unphosphorylated STATs (uSTATs), such as uSTAT3, may stabilize heterochromatin by specifically interacting with HP1. (B) All human STAT transcription factors contain the HP1-binding motif PxVxL/I (highlighted in black). Shown is an amino acid sequence alignment of the regions surrounding the HP1-binding motif in seven members of the human STAT protein family.