Role of SARS-CoV-2 in Altering the RNA-Binding Protein and miRNA-Directed Post-Transcriptional Regulatory Networks in Humans.

Rajneesh Srivastava,Mansi Srivastava,Sarath Chandra Janga,Swapna Vidhur Daulatabad

doi:10.3390/ijms21197090

Abstract

The outbreak of a novel coronavirus SARS-CoV-2 responsible for the COVID-19 pandemic has caused a worldwide public health emergency. Due to the constantly evolving nature of the coronaviruses, SARS-CoV-2-mediated alterations on post-transcriptional gene regulations across human tissues remain elusive. In this study, we analyzed publicly available genomic datasets to systematically dissect the crosstalk and dysregulation of the human post-transcriptional regulatory networks governed by RNA-binding proteins (RBPs) and micro-RNAs (miRs) due to SARS-CoV-2 infection. We uncovered that 13 out of 29 SARS-CoV-2-encoded proteins directly interacted with 51 human RBPs, of which the majority of them were abundantly expressed in gonadal tissues and immune cells. We further performed a functional analysis of differentially expressed genes in mock-treated versus SARS-CoV-2-infected lung cells that revealed enrichment for the immune response, cytokine-mediated signaling, and metabolism-associated genes. This study also characterized the alternative splicing events in SARS-CoV-2-infected cells compared to the control, demonstrating that skipped exons and mutually exclusive exons were the most abundant events that potentially contributed to differential outcomes in response to the viral infection. A motif enrichment analysis on the RNA genomic sequence of SARS-CoV-2 clearly revealed the enrichment for RBPs such as SRSFs, PCBPs, ELAVs, and HNRNPs, suggesting the sponging of RBPs by the SARS-CoV-2 genome. A similar analysis to study the interactions of miRs with SARS-CoV-2 revealed functionally important miRs that were highly expressed in immune cells, suggesting that these interactions may contribute to the progression of the viral infection and modulate the host immune response across other human tissues. Given the need to understand the interactions of SARS-CoV-2 with key post-transcriptional regulators in the human genome, this study provided a systematic computational analysis to dissect the role of dysregulated post-transcriptional regulatory networks controlled by RBPs and miRs across tissue types during a SARS-CoV-2 infection.

Highlights

An outbreak of coronavirus disease (COVID-19) caused by the newly discovered severe acute respiratory syndrome coronavirus (SARS-CoV-2) started in December 2019 in the city of Wuhan, Hubei Province, China
We obtained the affinity purification-mass spectrometry (AP-MS)-based SARS-CoV-2 and human proteins interaction network established in HEK293 cells [23] and investigated the human ribonucleic acid (RNA)-binding proteins (RBPs) that directly interact with the viral proteins
These results suggest that several human RBPs that come into direct contact with SARS-CoV-2 proteins could contribute to virus assembly and export and could be implicated as therapeutic targets

Summary

Introduction

An outbreak of coronavirus disease (COVID-19) caused by the newly discovered severe acute respiratory syndrome coronavirus (SARS-CoV-2) started in December 2019 in the city of Wuhan, Hubei Province, China. In the past two decades, coronavirus outbreaks have resulted in viral epidemics, including a severe acute respiratory syndrome (SARS-CoV) in 2002 with a fatality of 10% and the Middle East respiratory syndrome (MERS-CoV) in 2012 with fatality of 36% [1,2,3,4]. Both SARS-CoV and MERS-CoV were zoonotic viruses originating in bats and camels, respectively [5,6]. Rapid efforts have illustrated the molecular features of SARS-CoV-2 that enable it to hijack the host cellular machinery and facilitates its genomic replication and assembly into new virions during the infection process [13,14,15,16]

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Results

Conclusion