RNA-GPS Predicts SARS-CoV-2 RNA Localization to Host Mitochondria and Nucleolus

Abstract

The SARS-CoV-2 coronavirus is driving a global pandemic, but its biological mechanisms are less well understood. SARS-CoV-2 is an RNA virus whose multiple genomic and subgenomic RNA (sgRNA) transcripts hijack the host cell's machinery, located across distinct cytotopic locations. Subcellular localization of its viral RNA could play important roles in viral replication and host antiviral immune response. Here we perform computational modeling of SARS-CoV-2 viral RNA localization across eight subcellular neighborhoods. We compare hundreds of SARS-CoV-2 genomes to the human transcriptome and other coronaviruses and perform systematic sub-sequence analyses to identify the responsible signals. Using state-of-the-art machine learning models, we predict that the SARS-CoV-2 RNA genome and all sgRNAs are enriched in the host mitochondrial matrix and nucleolus. The 5' and 3' viral untranslated regions possess the strongest and most distinct localization signals. We discuss the mitochondrial localization signal in relation to the formation of double-membrane vesicles, a critical stage in the coronavirus life cycle. Our computational analysis serves as a hypothesis generation tool to suggest models for SARS-CoV-2 biology and inform experimental efforts to combat the virus.

Rapid endothelial infection, endothelialitis and vascular damage characterise SARS-CoV-2 infection in a human lung-on-chip model

“…These differences could be due to differences in the mode of uptake -NRP1 is also a receptor for VEGF signalling 39 , or differences in the intracellular localization of viral RNA and RNA replication, or differences in the levels of translation of viral proteins. We observe instances of co-localisation of viral RNA and S protein with the nucleus, which is consistent with bioinformatic predictions using algorithms for RNA localisation 40 , but has not been reported in studies using cell lines with productive infections. These atypical sub-cellular localisations may be characteristic of persistent infection and merit further investigation.…”

SARS-CoV-2 induces a unique mitochondrial transcriptome signature

“…Recent reports have predicted that SARS-CoV-2 RNA localizes to the mitochondrion. 23 An additional prereview report hinted that it is plausible that SARS-CoV-2 RNA can anneal with mitochondrial deubuiquitanse USP30, a subunit of ubuquiting protein ligase complex FBX021 (https://www.biorxiv.org/content/10.1101/2020.04.08.031856v3.full). SARS-CoV-2 RNA acting as an…”

SARS-CoV-2: From Structure to Pathology, Host Immune Response and Therapeutic Management

“…Recombination can occur between two viral strains of the Coronaviridae family, but also with an unrelated virus. Recombination events, as well as events associated with the reassortment of genomic segments to influenza A viruses, generate a new virus, which, if transmitted to humans, may have a very high pathogenic potential [ 43 ]. In nature, such recombination (in Coronaviridae ) or re-assortment of genomic segments (in influenza A) processes have an unknown frequency, but some of them generate new viruses with an increased capacity to disseminate in new hosts.…”

“…Patients with comorbidities or with a special ACE2 polymorphism, which are more susceptible to SARS-CoV-2 infection also exhibit mitochondrial disfunctions. The exonic variant—G8790A is significantly more frequent in European and South Asian populations [ 72 ], while the G/G genotype may decrease ACE2 expression on the cell surface up to 50% [ 43 , 73 ].…”