SARS-CoV-2 helicase might interfere with cellular nonsense-mediated RNA decay: insights from a bioinformatics study

Abstract

Background: Viruses employ diverse strategies to interfere with host defense mechanisms, including the production of proteins that mimic or resemble host proteins. This study aimed to analyze the similarities between SARS-CoV-2 and human proteins, investigate their impact on virus-host interactions, and elucidate underlying mechanisms.

Results: Comparing the proteins of SARS-CoV-2 with human and mammalian proteins revealed sequence and structural similarities between viral helicase with human UPF1. The latter is a protein that is involved in nonsense-mediated RNA decay (NMD), an mRNA surveillance pathway which also acts as a cellular defense mechanism against viruses. Protein sequence similarities were also observed between viral nsp3 and human Poly ADP-ribose polymerase (PARP) family of proteins. Gene set enrichment analysis on transcriptomic data derived from SARS-CoV-2 positive samples illustrated the enrichment of genes belonging to the NMD pathway compared with control samples. Moreover, comparing transcriptomic data from SARS-CoV-2-infected samples with transcriptomic data derived from UPF1 knockdown cells demonstrated a significant overlap between datasets.

Conclusions: These findings suggest that helicase/UPF1 sequence and structural similarity might have the ability to interfere with the NMD pathway with pathogenic and immunological implications.

Keywords: Coronaviridae; Helicase; Nonsense-mediated RNA decay; RNA surveillance; SARS-CoV-2.

Fig. 1

SARS-CoV-2 Nsp3 and helicase reveal higher sequence similarities with human/mammalian proteins. Results of the 1st (A) and 3rd (B) iterations of DELTA-BLAST comparing SARS-CoV-2 protein sequences with Homo sapiens RefSeq proteins have been shown as negative log E values/alignment scores. Likewise, results of the 1st (C) and 3rd (D) iterations of DELTA-BLAST comparing SARS-CoV-2 proteins against mammalian RefSeq proteins are shown. Below every SARS-COV-2 protein, the name of the aligned human or mammalian protein (together with the species for the latter) is shown with red fonts. For each query only the highest log E value/score has been shown

Fig. 2

SARS-CoV-2 helicase protein sequence similarities with human proteins. Results of the 1st and 3rd iterations of DELTA-BLAST comparing SARS-CoV-2 helicase (A and B) or nsp3 (C and D) with Homo sapiens RefSeq proteins

Fig. 3

Structural comparison and schematic representation of domains of human UPF1 and coronaviral helicases. Representation of pairwise structure alignment of SARS-CoV-2 with UPF1 (A). Data extracted from pairwise structure alignment of SARS-CoV-2, SARS-CoV, and MERS-CoV helicase protein with UPF1 and CH domain (B). Schematic representation of domains of human UPF1 and coronaviral helicases (C). Pairwise structure alignment of SARS-CoV-2, SARS-CoV, and MERS-CoV with UPF1 CH domain (D). RMSD: Root Mean Square Deviation

Fig. 4

GSEA analyses on different SARS-CoV-2-infected cells/tissues. GSEA analyses of GSE155974 (A), GSE171110 (B), and GSE157103 (C) GSE182917 (D). All GSEA analyses, except one, show negative enrichment of NMD pathway in samples infected with SARS-CoV-2

Fig. 5

Venn diagrams showing the similarity in DEGs between Colombo et al. study and SARS-CoV-2-infected cells/tissues. Transcripts showing significant alterations (FDR < 0.05) between Colombo et al. study and GSE155974 (A), GSE171110 (B), and GSE157103 (C) GSE182917 (D) studies are shown. Table shows p values for Up and down-DEGs shared by the two studies