SARS-CoV-2 selectively induces the expression of unproductive splicing isoforms of interferon, class I MHC and splicing machinery genes
SARS-CoV-2 selectively induces the expression of unproductive splicing isoforms of interferon, class I MHC and splicing machinery genes
Abstract Splicing is a highly conserved, intricate mechanism intimately linked to transcription elongation, serving as a pivotal regulator of gene expression. Alternative splicing may generate specific transcripts incapable of undergoing translation into proteins, designated as unproductive. A plethora of respiratory viruses, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), strategically manipulate the host’s splicing machinery to circumvent antiviral responses. During the infection, SARS-CoV-2 effectively suppresses interferon (IFN) expression, leading to B cell and CD8+ T cell leukopenia, while simultaneously increasing the presence of macrophages and neutrophils in patients with severe COVID-19. In this study, we integrated publicly available omics datasets to systematically analyze transcripts at the isoform level and delineate the nascent-peptide translatome landscapes of SARS-CoV-2-infected human cells. Our findings reveal a hitherto uncharacterized mechanism whereby SARS-CoV-2 infection induces the predominant expression of unproductive splicing isoforms in key IFN signaling genes, interferon-stimulated genes (ISGs), class I MHC genes, and splicing machinery genes, including IRF7, OAS3, HLA-B, and HNRNPH1. In stark contrast, cytokine and chemokine genes, such as IL6, CXCL8, and TNF, predominantly express productive (protein-coding) splicing isoforms in response to SARS-CoV-2 infection. We postulate that SARS-CoV-2 employs a previously unreported tactic of exploiting the host splicing machinery to bolster viral replication and subvert the immune response by selectively upregulating unproductive splicing isoforms from antigen presentation and antiviral response genes. Our study sheds new light on the molecular interplay between SARS-CoV-2 and the host immune system, offering a foundation for the development of novel therapeutic strategies to combat COVID-19.
Queiroz L¨2cio Rezende、Polidoro Alves Barbosa Rafael、L¨1scher Dias Thomaz、Del-Bem Luiz Eduardo、Castro ¨acaro、Franco Gl¨?ria Regina、Nakaya Helder、Mamede Costa Andrade da Concei??o Izabela、Toledo Nayara Evelin de
Departamento de Bioqu¨amica e Imunologia, Instituto de Ci¨oncias Biol¨?gicas, Universidade Federal de Minas GeraisDepartment of Pediatrics, Indiana University School of MedicineDepartamento de Bioqu¨amica e Imunologia, Instituto de Ci¨oncias Biol¨?gicas, Universidade Federal de Minas Gerais||Departamento de An¨￠lises Cl¨anicas e Toxicol¨?gicas, Faculdade de Ci¨oncias Farmac¨outicas Universidade de S?o PauloDepartmento de Botanica, Instituto de Ci¨oncias Biol¨?gicas, Universidade Federal de Minas Gerais||Department of Plant Biology, Michigan State UniversityDepartamento de An¨￠lises Cl¨anicas e Toxicol¨?gicas, Faculdade de Ci¨oncias Farmac¨outicas Universidade de S?o PauloDepartamento de Bioqu¨amica e Imunologia, Instituto de Ci¨oncias Biol¨?gicas, Universidade Federal de Minas GeraisDepartamento de An¨￠lises Cl¨anicas e Toxicol¨?gicas, Faculdade de Ci¨oncias Farmac¨outicas Universidade de S?o Paulo||Scientific Platform Pasteur-University of S?o Paulo||Hospital Israelita Albert EinsteinDepartamento de Bioqu¨amica e Imunologia, Instituto de Ci¨oncias Biol¨?gicas, Universidade Federal de Minas GeraisDepartamento de Bioqu¨amica e Imunologia, Instituto de Ci¨oncias Biol¨?gicas, Universidade Federal de Minas Gerais
基础医学分子生物学微生物学
Queiroz L¨2cio Rezende,Polidoro Alves Barbosa Rafael,L¨1scher Dias Thomaz,Del-Bem Luiz Eduardo,Castro ¨acaro,Franco Gl¨?ria Regina,Nakaya Helder,Mamede Costa Andrade da Concei??o Izabela,Toledo Nayara Evelin de.SARS-CoV-2 selectively induces the expression of unproductive splicing isoforms of interferon, class I MHC and splicing machinery genes[EB/OL].(2025-03-28)[2025-05-01].https://www.biorxiv.org/content/10.1101/2023.04.12.536671.点此复制
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