SARS-CoV-2 nucleocapsid protein binds host mRNAs and attenuates stress granules to impair host stress response
Syed Nabeel-Shah,
Hyunmin Lee,
Nujhat Ahmed,
Giovanni L. Burke,
Shaghayegh Farhangmehr,
Kanwal Ashraf,
Shuye Pu,
Ulrich Braunschweig,
Guoqing Zhong,
Hong Wei,
Hua Tang,
Jianyi Yang,
Edyta Marcon,
Benjamin J. Blencowe,
Zhaolei Zhang,
Jack F. Greenblatt
Affiliations
Syed Nabeel-Shah
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
Hyunmin Lee
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Computer Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada
Nujhat Ahmed
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
Giovanni L. Burke
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
Shaghayegh Farhangmehr
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
Kanwal Ashraf
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada
Shuye Pu
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada
Ulrich Braunschweig
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada
Guoqing Zhong
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada
Hong Wei
School of Mathematical Sciences, Nankai University, Tianjin 300071, China
Hua Tang
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada
Jianyi Yang
School of Mathematical Sciences, Nankai University, Tianjin 300071, China
Edyta Marcon
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada
Benjamin J. Blencowe
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
Zhaolei Zhang
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Computer Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada
Jack F. Greenblatt
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Corresponding author
Summary: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N) protein is essential for viral replication, making it a promising target for antiviral drug and vaccine development. SARS-CoV-2 infected patients exhibit an uncoordinated immune response; however, the underlying mechanistic details of this imbalance remain obscure. Here, starting from a functional proteomics workflow, we cataloged the protein–protein interactions of SARS-CoV-2 proteins, including an evolutionarily conserved specific interaction of N with the stress granule resident proteins G3BP1 and G3BP2. N localizes to stress granules and sequesters G3BPs away from their typical interaction partners, thus attenuating stress granule formation. We found that N binds directly to host mRNAs in cells, with a preference for 3′ UTRs, and modulates target mRNA stability. We show that the N protein rewires the G3BP1 mRNA-binding profile and suppresses the physiological stress response of host cells, which may explain the imbalanced immune response observed in SARS-CoV-2 infected patients.
