I(nsp1)ecting SARS-CoV-2-ribosome interactions

Abstract

While SARS-CoV-2 is causing modern human history's most serious health crisis and upending our way of life, clinical and basic research on the virus is advancing rapidly, leading to fascinating discoveries. Two studies have revealed how the viral virulence factor, nonstructural protein 1 (Nsp1), binds human ribosomes to inhibit host cell translation. Here, we examine the main conclusions on the molecular activity of Nsp1 and its role in suppressing innate immune responses. We discuss different scenarios potentially explaining how the viral RNA can bypass its own translation blockage and speculate on the suitability of Nsp1 as a therapeutic target.

Fig. 1. Nsp1 interaction with the ribosome.

a Schematic of SARS-CoV-2 genome organisation with the whole genome depicted at the top, Nsp1 coding sequence in the middle, and a sequence alignment of Nsp1 C-terminal domain of SARS-CoV-2, SARS-CoV-1, and MERS-CoV in the lower part of the panel. The two alpha helices and the KH motif are marked by bars and an arrow, respectively. Colour coding of amino acids corresponds to default settings of the ClustalX alignment tool. b Cartoon depicting the interaction between Nsp1 and the 40S ribosomal subunit, as revealed by the structural data. The C-terminal helices anchor Nsp1 in the mRNA entry channel, thereby blocking access for host transcripts (schematically represented in grey). The globular N-terminus is not sufficiently resolved in the structures to be able to assign a clear position and function.

Fig. 2. Nsp1 impacts host gene expression by several mechanisms.

Schematic representation of the main activities and mechanisms through which Nsp1 is thought to act in order to favour gene expression to viral transcripts, without shutting down mRNA translation completely. a Nsp1 may have a role in shifting the balance between viral and cellular RNAs in its favour, by inducing the cleavage/decapping of host mRNAs, which leads to their degradation by cellular nucleases. b The viral 5′ UTR (and in particular stem loop SL1) is likely a critical factor in directing ribosomes to the viral transcripts and overriding the translation block. Moreover, it has also been proposed that through Nsp1 autoregulation a total block of host mRNA translation may be prevented.