Abstract
Conventionally, eukaryotic mRNAs were thought to be monocistronic, leading to the translation of a single protein. However, large-scale proteomics have led to a massive identification of proteins translated from mRNAs of alternative ORF (AltORFs), in addition to the predicted proteins issued from the reference ORF or from ncRNAs. These alternative proteins (AltProts) are not represented in the conventional protein databases and this “ghost proteome” was not considered until recently. Some of these proteins are functional and there is growing evidence that they are involved in central functions in physiological and physiopathological context. Based on our experience with AltProts, we were interested in finding out their interaction with the viral protein coming from the SARS-CoV-2 virus, responsible for the 2020 COVID-19 outbreak. Thus, we have scrutinized the recently published data by Krogan and coworkers (2020) on the SARS-CoV-2 interactome with host cells by affinity purification in co-immunoprecipitation (co-IP) in the perspective of drug repurposing. The initial work revealed the interaction between 332 human cellular reference proteins (RefProts) with the 27 viral proteins. Re-interrogation of this data using 23 viral targets and including AltProts, followed by enrichment of the interaction networks, leads to identify 218 RefProts (in common to initial study), plus 56 AltProts involved in 93 interactions. This demonstrates the necessity to take into account the ghost proteome for discovering new therapeutic targets, and establish new therapeutic strategies. Missing the ghost proteome in the drug metabolism and pharmacokinetic (DMPK) drug development pipeline will certainly be a major limitation to the establishment of efficient therapies.
Highlights
Because proteins are the end products of gene expression, they have a major impact on cell regulation, being main targets for the development of new drugs and therapies
Sapiens alternative proteins (GRCh38.p5, Assembly: GCA_000001405.20). This database compiles all proteins coming from non-coding regions of mRNA, such as 5 &3 untranslated region (UTR), shift in reading frame in +2 or +3, and the proteins discovered coding in non-coding RNA (ncRNA)
We studied the presence of potential AltProt involved in the interaction between the virus and the host cell, representing the possible role of the ghost proteome during a viral infection
Summary
Because proteins are the end products of gene expression, they have a major impact on cell regulation, being main targets for the development of new drugs and therapies. Identified AltProts are found to be translated, either from mRNA including from the non-coding 5 & 3 UTR or a frame shift (+1 or 2 nucleotides) in the CDS of the RefProt, or from ncRNA [9].
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