The Emerging Role of SARS-CoV-2 Nonstructural Protein 1 (nsp1) in Epigenetic Regulation of Host Gene Expression

Overview

Journal FEMS Microbiol Rev

Publisher Oxford University Press

Specialty Microbiology

Date 2024 Sep 4

PMID 39231808

Authors

Konstantin I Ivanov

Haibin Yang

Ruixue Sun

Chunmei Li

Deyin Guo

Affiliations

Soon will be listed here.

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.

Citing Articles

SARS-CoV-2 Evolution: Implications for Diagnosis, Treatment, Vaccine Effectiveness and Development.

Angius F, Puxeddu S, Zaimi S, Canton S, Nematollahzadeh S, Pibiri A Vaccines (Basel). 2025; 13(1).

PMID: 39852796 PMC: 11769326. DOI: 10.3390/vaccines13010017.

References

Gan H, Serra-Cardona A, Hua X, Zhou H, Labib K, Yu C . The Mcm2-Ctf4-Polα Axis Facilitates Parental Histone H3-H4 Transfer to Lagging Strands. Mol Cell. 2018; 72(1):140-151.e3. PMC: 6193272. DOI: 10.1016/j.molcel.2018.09.001. View

Abaeva I, Arhab Y, Miscicka A, Hellen C, Pestova T . In vitro reconstitution of SARS-CoV-2 Nsp1-induced mRNA cleavage reveals the key roles of the N-terminal domain of Nsp1 and the RRM domain of eIF3g. Genes Dev. 2023; 37(17-18):844-860. PMC: 10620056. DOI: 10.1101/gad.350829.123. View

Nasheuer H, Onwubiko N . Lagging Strand Initiation Processes in DNA Replication of Eukaryotes-Strings of Highly Coordinated Reactions Governed by Multiprotein Complexes. Genes (Basel). 2023; 14(5). PMC: 10218536. DOI: 10.3390/genes14051012. View

Zheng Y, Liu X, Le W, Xie L, Li H, Wen W . A human circulating immune cell landscape in aging and COVID-19. Protein Cell. 2020; 11(10):740-770. PMC: 7417788. DOI: 10.1007/s13238-020-00762-2. View

Barrero J, Gonzalez-Bayon R, Del Pozo J, Ponce M, Micol J . INCURVATA2 encodes the catalytic subunit of DNA Polymerase alpha and interacts with genes involved in chromatin-mediated cellular memory in Arabidopsis thaliana. Plant Cell. 2007; 19(9):2822-38. PMC: 2048701. DOI: 10.1105/tpc.107.054130. View

Kandwal S, Fayne D . Genetic conservation across SARS-CoV-2 non-structural proteins - Insights into possible targets for treatment of future viral outbreaks. Virology. 2023; 581:97-115. PMC: 9999249. DOI: 10.1016/j.virol.2023.02.011. View

Shi S, Larson K, Guo D, Lim S, Dutta P, Yan S . Drosophila STAT is required for directly maintaining HP1 localization and heterochromatin stability. Nat Cell Biol. 2008; 10(4):489-96. PMC: 3083919. DOI: 10.1038/ncb1713. View

Brown M, Bollum F, Chang L . Intracellular localization of DNA polymerase alpha. Proc Natl Acad Sci U S A. 1981; 78(5):3049-52. PMC: 319497. DOI: 10.1073/pnas.78.5.3049. View

Shen X, Geng R, Li Q, Chen Y, Li S, Wang Q . ACE2-independent infection of T lymphocytes by SARS-CoV-2. Signal Transduct Target Ther. 2022; 7(1):83. PMC: 8914143. DOI: 10.1038/s41392-022-00919-x. View

10.

Fisher T, Gluck A, Narayanan K, Kuroda M, Nachshon A, Hsu J . Parsing the role of NSP1 in SARS-CoV-2 infection. Cell Rep. 2022; 39(11):110954. PMC: 9133101. DOI: 10.1016/j.celrep.2022.110954. View

11.

Zhou Y, Wang T . A coordinated temporal interplay of nucleosome reorganization factor, sister chromatin cohesion factor, and DNA polymerase alpha facilitates DNA replication. Mol Cell Biol. 2004; 24(21):9568-79. PMC: 522230. DOI: 10.1128/MCB.24.21.9568-9579.2004. View

12.

Zhang L, Lu Q, Chang C . Epigenetics in Health and Disease. Adv Exp Med Biol. 2020; 1253:3-55. DOI: 10.1007/978-981-15-3449-2_1. View

13.

Giroux N, Ding S, McClain M, Burke T, Petzold E, Chung H . Differential chromatin accessibility in peripheral blood mononuclear cells underlies COVID-19 disease severity prior to seroconversion. Sci Rep. 2022; 12(1):11714. PMC: 9271053. DOI: 10.1038/s41598-022-15668-8. View

14.

Lachner M, OCarroll D, Rea S, Mechtler K, Jenuwein T . Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature. 2001; 410(6824):116-20. DOI: 10.1038/35065132. View

15.

Meyer T, Gavenis K, Vinkemeier U . Cell type-specific and tyrosine phosphorylation-independent nuclear presence of STAT1 and STAT3. Exp Cell Res. 2001; 272(1):45-55. DOI: 10.1006/excr.2001.5405. View

16.

Miao Z, Tidu A, Eriani G, Martin F . Secondary structure of the SARS-CoV-2 5'-UTR. RNA Biol. 2020; 18(4):447-456. PMC: 7544965. DOI: 10.1080/15476286.2020.1814556. View

17.

Simon A, Zhou J, Perera R, van Deursen F, Evrin C, Ivanova M . A Ctf4 trimer couples the CMG helicase to DNA polymerase α in the eukaryotic replisome. Nature. 2014; 510(7504):293-297. PMC: 4059944. DOI: 10.1038/nature13234. View

18.

Snijder E, Bredenbeek P, Dobbe J, Thiel V, Ziebuhr J, Poon L . Unique and conserved features of genome and proteome of SARS-coronavirus, an early split-off from the coronavirus group 2 lineage. J Mol Biol. 2003; 331(5):991-1004. PMC: 7159028. DOI: 10.1016/s0022-2836(03)00865-9. View

19.

Noguera-Castells A, Parra J, Davalos V, Garcia-Prieto C, Veselinova Y, Perez-Mies B . Epigenetic Fingerprint of the SARS-CoV-2 Infection in the Lung of Lethal COVID-19. Chest. 2023; 165(4):820-824. DOI: 10.1016/j.chest.2023.10.032. View

20.

Zhang J, Cruz-Cosme R, Zhuang M, Liu D, Liu Y, Teng S . A systemic and molecular study of subcellular localization of SARS-CoV-2 proteins. Signal Transduct Target Ther. 2020; 5(1):269. PMC: 7670843. DOI: 10.1038/s41392-020-00372-8. View