The role of NSP6 in the biogenesis of the SARS-CoV-2 replication organelle

Simona Ricciardi, Andrea Maria Guarino, Laura Giaquinto, Elena V. Polishchuk, Michele Santoro, Giuseppe Di Tullio, Cathal Wilson, Francesco Panariello, Vinicius C. Soares, Suelen S. G. Dias, Julia C. Santos, Thiago M. L. Souza, Giovanna Fusco, Maurizio Viscardi, Sergio Brandi, Patrícia T. Bozza, Roman S. Polishchuk (), Rossella Venditti () and Maria Antonietta De Matteis ()
Additional contact information
Simona Ricciardi: Telethon Institute of Genetics and Medicine (TIGEM)
Andrea Maria Guarino: Telethon Institute of Genetics and Medicine (TIGEM)
Laura Giaquinto: Telethon Institute of Genetics and Medicine (TIGEM)
Elena V. Polishchuk: Telethon Institute of Genetics and Medicine (TIGEM)
Michele Santoro: Telethon Institute of Genetics and Medicine (TIGEM)
Giuseppe Di Tullio: Telethon Institute of Genetics and Medicine (TIGEM)
Cathal Wilson: Telethon Institute of Genetics and Medicine (TIGEM)
Francesco Panariello: Telethon Institute of Genetics and Medicine (TIGEM)
Vinicius C. Soares: Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (FIOCRUZ)
Suelen S. G. Dias: Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (FIOCRUZ)
Julia C. Santos: Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (FIOCRUZ)
Thiago M. L. Souza: Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (FIOCRUZ)
Giovanna Fusco: Istituto Zooprofilattico Sperimentale del Mezzogiorno
Maurizio Viscardi: Istituto Zooprofilattico Sperimentale del Mezzogiorno
Sergio Brandi: Istituto Zooprofilattico Sperimentale del Mezzogiorno
Patrícia T. Bozza: Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (FIOCRUZ)
Roman S. Polishchuk: Telethon Institute of Genetics and Medicine (TIGEM)
Rossella Venditti: Telethon Institute of Genetics and Medicine (TIGEM)
Maria Antonietta De Matteis: Telethon Institute of Genetics and Medicine (TIGEM)

Nature, 2022, vol. 606, issue 7915, 761-768

Abstract: Abstract SARS-CoV-2, like other coronaviruses, builds a membrane-bound replication organelle to enable RNA replication1. The SARS-CoV-2 replication organelle is composed of double-membrane vesicles (DMVs) that are tethered to the endoplasmic reticulum (ER) by thin membrane connectors2, but the viral proteins and the host factors involved remain unknown. Here we identify the viral non-structural proteins (NSPs) that generate the SARS-CoV-2 replication organelle. NSP3 and NSP4 generate the DMVs, whereas NSP6, through oligomerization and an amphipathic helix, zippers ER membranes and establishes the connectors. The NSP6(ΔSGF) mutant, which arose independently in the Alpha, Beta, Gamma, Eta, Iota and Lambda variants of SARS-CoV-2, behaves as a gain-of-function mutant with a higher ER-zippering activity. We identified three main roles for NSP6: first, to act as a filter in communication between the replication organelle and the ER, by allowing lipid flow but restricting the access of ER luminal proteins to the DMVs; second, to position and organize DMV clusters; and third, to mediate contact with lipid droplets (LDs) through the LD-tethering complex DFCP1–RAB18. NSP6 thus acts as an organizer of DMV clusters and can provide a selective means of refurbishing them with LD-derived lipids. Notably, both properly formed NSP6 connectors and LDs are required for the replication of SARS-CoV-2. Our findings provide insight into the biological activity of NSP6 of SARS-CoV-2 and of other coronaviruses, and have the potential to fuel the search for broad antiviral agents.

Date: 2022
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DOI: 10.1038/s41586-022-04835-6

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