SARS-CoV-2 Encodes a PPxY Late Domain Motif Known to Enhance Budding and Spread in Enveloped RNA Viruses

Abstract

Currently, the global COVID-19 (Coronavirus Disease-2019) pandemic is affecting the health and/or socioeconomic life of almost each people in the world. Finding vaccines and therapeutics is urgent but without forgetting to elucidate the molecular mechanisms that allow some viruses to become dangerous for humans. Here, analysis of all proteins of SARS-CoV-2 revealed a unique PPxY Late (L) domain motif 25PPAY28 in spike protein inside hot disordered loop predicted subject to phosphorylation and binding. It was demonstrated in enveloped RNA viruses that PPxY motif recruits Nedd4 E3 ubiquitin ligases and ultimately the ESCRT complex to enhance virus budding and release that means a high viral load, hence facilitating new infections. Note that PPxY motif is not present in proteins of SARS-CoV. This suggests that PPxY motif by its role in enhancing the viral load could explain why SARS-CoV-2 is more contagious than SARS-CoV. Of course, after the experimental verifications showing that PPxY motif plays the same role as reported for other enveloped RNA viruses, it could become an interesting target for the development of novel host-oriented antivirals therapeutics for preventing S protein to recruit Nedd4 E3 ubiquitin ligases partners.

Inhibition of HECT E3 ligases as potential therapy for COVID-19

“…Interestingly, the PPxY motif is not present in SARS-CoV proteins. The presence of the motif PPxY might contribute to explain why SARS-CoV-2 is more contagious compared to SARS-CoV 22 .…”

“…These domains provide a scaffold for recruiting protein substrates and regulators. Several viral proteins have been shown to recruit WW-domain host cell proteins of the NEDD4 family through PPxY motifs to facilitate their egression and diffusion 21,22 . Among them, WWP1 was found to interact with Ebola Virus VP40 to regulate egression suggesting that viral PPxY-host WW domainmediated interaction could represent a potential new target for host-oriented inhibitors of EBOV and other virus egression 23 .…”

SARS-CoV-2 3CLpro whole human proteome cleavage prediction and enrichment/depletion analysis

“…Although the former sequence is APNY and is likely not ubiquitinated in SARS-CoV, small molecule drugs targeting this interaction or related kinases may be useful treatments for COVID-19 as they have been for other RNA viruses. [155][156][157] Further research is required to compare these cleavages to the PLpro deubiquitinating activity and the specificity and function of distinct ubiquitin and other ubiquitin-like protein linkage sites. [158,159] Helicases make up approximately 1% of eukaryotic genes and are enriched in cleavages with many containing RNA-specific DEAD/DEAH boxes.…”

SARS-CoV-2 3CLpro whole human proteome cleavage prediction and enrichment/depletion analysis

“…Although the former sequence is APNY and is likely not ubiquitinated in SARS-CoV, small molecule drugs targeting this interaction or related kinases may be useful treatments for COVID-19 as they have been for other RNA viruses. 157 , 158 , 159 Further research is required to compare these cleavages to the PLpro deubiquitinating activity and the specificity and function of distinct ubiquitin and other ubiquitin-like protein linkage sites. 160 , 161 …”