tetano
Editor, Senior Moderator
iScience
. 2021 Dec 4;103562.
doi: 10.1016/j.isci.2021.103562. Online ahead of print.
SARS-CoV-2 Nucleocapsid protein attenuates stress granules and interacts with mRNAs to impair host stress response
Syed Nabeel-Shah[SUP] 1 2 [/SUP], Hyunmin Lee[SUP] 1 3 [/SUP], Nujhat Ahmed[SUP] 1 2 [/SUP], Giovanni L Burke[SUP] 1 2 [/SUP], Shaghayegh Farhangmehr[SUP] 1 2 [/SUP], Kanwal Ashraf[SUP] 1 [/SUP], Shuye Pu[SUP] 1 [/SUP], Ulrich Braunschweig[SUP] 1 [/SUP], Guoqing Zhong[SUP] 1 [/SUP], Hong Wei[SUP] 4 [/SUP], Hua Tang[SUP] 1 [/SUP], Jianyi Yang[SUP] 4 [/SUP], Edyta Marcon[SUP] 1 [/SUP], Benjamin J Blencowe[SUP] 1 2 [/SUP], Zhaolei Zhang[SUP] 1 2 3 [/SUP], Jack F Greenblatt[SUP] 1 2 [/SUP]
Affiliations
Abstract
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 catalogued 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.
Keywords: COVID-19; G3BP1; G3BP2; Gene regulation; N protein; Nucleocapsid; SARS-CoV-2; Stress granules; iCLIP; mRNA-binding.
. 2021 Dec 4;103562.
doi: 10.1016/j.isci.2021.103562. Online ahead of print.
SARS-CoV-2 Nucleocapsid protein attenuates stress granules and interacts with mRNAs to impair host stress response
Syed Nabeel-Shah[SUP] 1 2 [/SUP], Hyunmin Lee[SUP] 1 3 [/SUP], Nujhat Ahmed[SUP] 1 2 [/SUP], Giovanni L Burke[SUP] 1 2 [/SUP], Shaghayegh Farhangmehr[SUP] 1 2 [/SUP], Kanwal Ashraf[SUP] 1 [/SUP], Shuye Pu[SUP] 1 [/SUP], Ulrich Braunschweig[SUP] 1 [/SUP], Guoqing Zhong[SUP] 1 [/SUP], Hong Wei[SUP] 4 [/SUP], Hua Tang[SUP] 1 [/SUP], Jianyi Yang[SUP] 4 [/SUP], Edyta Marcon[SUP] 1 [/SUP], Benjamin J Blencowe[SUP] 1 2 [/SUP], Zhaolei Zhang[SUP] 1 2 3 [/SUP], Jack F Greenblatt[SUP] 1 2 [/SUP]
Affiliations
- PMID: 34901782
- PMCID: PMC8642831
- DOI: 10.1016/j.isci.2021.103562
Abstract
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 catalogued 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.
Keywords: COVID-19; G3BP1; G3BP2; Gene regulation; N protein; Nucleocapsid; SARS-CoV-2; Stress granules; iCLIP; mRNA-binding.