Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2

TLDR

SARS‑CoV‑2 hijacks host translation and its Nsp1 protein shuts down host mRNA synthesis, contributing to viral replication and disease severity. The study proposes targeting the Nsp1–ribosome binding pocket as a therapeutic strategy against COVID‑19. Cryo‑EM revealed that Nsp1 blocks the mRNA entry tunnel of the 40S ribosome, a mechanism confirmed in native complexes and shown to nearly abolish innate immune signaling. Thoms et al., Science, 2020, p.

Abstract

A viral block on host protein synthesis As the coronavirus disease 2019 (COVID-19) pandemic continues to cause devastation, scientists race to increase their understanding of the disease-causing severe acute respiratory syndrome coronavirus 2. Once inside host cells, not only does the virus hijack the cells' translational machinery to make viral proteins, but the virulence factor nonstructural protein 1 (Nsp1) also shuts down translation of host messenger RNA. Thoms et al. determined a 2.6-angstrom resolution cryo–electron microscopy structure of a reconstituted complex of Nsp1 bound to the human 40 S ribosomal subunit and showed that Nsp1 blocks the messenger RNA entry tunnel. A structural inventory of native Nsp1-ribosome complexes from human cells confirms this mechanism. Cellular studies show that the translational shutdown almost completely inhibits the innate immune response. The binding pocket on the ribosome may be a target for drugs to treat COVID-19. Science , this issue p. 1249