Host PDZ‐containing proteins targeted by SARS‐CoV‐2
Célia Caillet‐Saguya b✉, Fabien Durbessonc d, Veronica V. Rezelje f, Gergő Góglg h, Quang Dinh Trane f i j, Jean‐Claude Twizerek l, Marco Vignuzzie f, Renaud Vincentellic d, Nicolas Wolffa b✉
- aInstitut Pasteur, Unité Récepteurs-Canaux, UMR CNRS 3571, 75015 Paris, France
- bInstitut Pasteur Unité Récepteurs‐Canaux UMR CNRS 3571 Paris France
- cAFMB, UMR CNRS 7257, 13288 Marseille, France
- dAFMB, UMR CNRS 7257, Marseille, France
- eInstitut Pasteur, Unité Populations Virales et Pathogénèse, UMR CNRS 3569, 75015 Paris, France
- fInstitut Pasteur Unité Populations Virales et Pathogénèse UMR CNRS 3569 Paris France
- gIGBMC, INSERM U1258/ UMR CNRS 7104, 67404 Illkirch, France
- hIGBMC, INSERM U1258/UMR CNRS 7104, Illkirch, France
- iÉcole doctorale BioSPC, Université Paris Diderot, Sorbonne Paris Cité, Paris, France
- jÉcole doctorale BioSPC Université Paris Diderot Sorbonne Paris Cité France
- kGIGA Institute, Molecular Biology of Diseases, Viral Interactomes laboratory, University of Liege, B-400 Liege, Belgium
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Abstract
Small linear motifs targeting protein interacting domains called PSD-95/Dlg/ZO-1 (PDZ) have been identified at the C terminus of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins E, 3a, and N. Using a high-throughput approach of affinity-profiling against the full human PDZome, we identified sixteen human PDZ binders of SARS-CoV-2 proteins E, 3A, and N showing significant interactions with dissociation constants values ranging from 3 to 82 μm. Six of them (TJP1, PTPN13, HTRA1, PARD3, MLLT4, LNX2) are also recognized by SARS-CoV while three (NHERF1, MAST2, RADIL) are specific to SARS-CoV-2 E protein. Most of these SARS-CoV-2 protein partners are involved in cellular junctions/polarity and could be also linked to evasion mechanisms of the immune responses during viral infection. Among the binders of the SARS-CoV-2 proteins E, 3a, or N, seven significantly affect viral replication under knock down gene expression in infected cells. This PDZ profiling identifying human proteins potentially targeted by SARS-CoV-2 can help to understand the multifactorial severity of COVID19 and to conceive effective anti-coronaviral agents for therapeutic purposes.