Nucleolin mediates SARS-CoV-2 replication and viral-induced apoptosis of host cells

Vanessa F Merino; Yu Yan; Alvaro A Ordonez; C Korin Bullen; Albert Lee; Harumi Saeki; Krishanu Ray; Tao Huang; Sanjay K Jain; Martin G Pomper

doi:10.1016/j.antiviral.2023.105550

Nucleolin mediates SARS-CoV-2 replication and viral-induced apoptosis of host cells

Antiviral Res. 2023 Mar:211:105550. doi: 10.1016/j.antiviral.2023.105550. Epub 2023 Feb 3.

Authors

Vanessa F Merino¹, Yu Yan², Alvaro A Ordonez³, C Korin Bullen⁴, Albert Lee⁵, Harumi Saeki⁶, Krishanu Ray⁷, Tao Huang⁸, Sanjay K Jain⁴, Martin G Pomper⁵

Affiliations

¹ Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: vmerino1@jhmi.edu.
² Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
³ Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: aordone2@jhmi.edu.
⁴ Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Department of Human Pathology, Faculty of Medicine, Juntendo University, Tokyo, Japan.
⁷ Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA; Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
⁸ Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Abstract

Host-oriented antiviral therapeutics are promising treatment options to combat COVID-19 and its emerging variants. However, relatively little is known about the cellular proteins hijacked by SARS-CoV-2 for its replication. Here we show that SARS-CoV-2 induces expression and cytoplasmic translocation of the nucleolar protein, nucleolin (NCL). NCL interacts with SARS-CoV-2 viral proteins and co-localizes with N-protein in the nucleolus and in stress granules. Knockdown of NCL decreases the stress granule component G3BP1, viral replication and improved survival of infected host cells. NCL mediates viral-induced apoptosis and stress response via p53. SARS-CoV-2 increases NCL expression and nucleolar size and number in lungs of infected hamsters. Inhibition of NCL with the aptamer AS-1411 decreases viral replication and apoptosis of infected cells. These results suggest nucleolin as a suitable target for anti-COVID therapies.

Keywords: Aptamer; COVID; Nucleolin; Nucleoprotein; SARS-CoV-2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis
COVID-19*
DNA Helicases
Humans
Nucleolin
Phosphoproteins / metabolism
Poly-ADP-Ribose Binding Proteins
RNA Helicases / metabolism
RNA Recognition Motif Proteins
SARS-CoV-2* / metabolism
Virus Replication

Substances

DNA Helicases
RNA Recognition Motif Proteins
Poly-ADP-Ribose Binding Proteins
RNA Helicases
Phosphoproteins
G3BP1 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding