SARS-CoV-2 targets ribosomal RNA biogenesis

• Published in: Cell reports (Cambridge) Vol. 43; no. 3; p. 113891
• Main Authors: Yerlici, V. Talya, Astori, Audrey, Kejiou, Nevraj S., Jordan, Chris A., Khosraviani, Negin, Chan, Janet N.Y., Hakem, Razqallah, Raught, Brian, Palazzo, Alexander F., Mekhail, Karim
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.03.2024; Elsevier
• Subjects: COVID-19 - metabolism; CP: Microbiology; Humans; Molecular biology; non-structural protein 1 (Nsp1); nucleolus; ribosomal RNA (rRNA); ribosome biogenesis; Ribosomes - metabolism; RNA processing; RNA, Ribosomal - metabolism; SARS-CoV-2; SARS-CoV-2 - genetics; translation; Viral Nonstructural Proteins - metabolism; Viral Proteins - metabolism; SARS-CoV-2; non-structural protein 1 (Nsp1); CP: Microbiology; nucleolus; translation; RNA processing; Molecular biology; ribosomal RNA (rRNA); ribosome biogenesis
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.113891

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hinders host gene expression, curbing defenses and licensing viral protein synthesis and virulence. During SARS-CoV-2 infection, the virulence factor non-structural protein 1 (Nsp1) targets the mRNA entry channel of mature cytoplasmic ribosomes, limiting translation. We show that Nsp1 also restrains translation by targeting nucleolar ribosome biogenesis. SARS-CoV-2 infection disrupts 18S and 28S ribosomal RNA (rRNA) processing. Expression of Nsp1 recapitulates the processing defects. Nsp1 abrogates rRNA production without altering the expression of critical processing factors or nucleolar organization. Instead, Nsp1 localizes to the nucleolus, interacting with precursor-rRNA and hindering its maturation separately from the viral protein’s role in restricting mature ribosomes. Thus, SARS-CoV-2 Nsp1 limits translation by targeting ribosome biogenesis and mature ribosomes. These findings revise our understanding of how SARS-CoV-2 Nsp1 controls human protein synthesis, suggesting that efforts to counter Nsp1’s effect on translation should consider the protein’s impact from ribosome manufacturing to mature ribosomes. [Display omitted] •SARS-CoV-2 Nsp1 localizes to the nucleolus, interacting with precursor rRNA•Nsp1 restrains nascent translation by disrupting rRNA processing and mature ribosomes•Repression of rRNA processing by Nsp1 is separable from mature ribosome inhibition Yerlici et al. report that SARS-CoV-2 Nsp1 localizes to the nucleolus and restrains human protein synthesis by thwarting the processing of ribosomal RNA molecules critical to ribosome manufacture. They show that SARS-CoV-2 Nsp1 represses host protein synthesis by interfering with ribosome production and mature ribosomes.