SARS-CoV-2 Envelope (E) protein interacts with PDZ-domain-2 of host tight junction protein ZO1

• Published in: PloS one Vol. 16; no. 6; p. e0251955
• Main Authors: Shepley-McTaggart, Ariel, Sagum, Cari A, Oliva, Isabela, Rybakovsky, Elizabeth, DiGuilio, Katie, Liang, Jingjing, Bedford, Mark T, Cassel, Joel, Sudol, Marius, Mullin, James M, Harty, Ronald N
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.06.2021; Public Library of Science (PLoS)
• Subjects: Amino acids; Biology and life sciences; Coronavirus Envelope Proteins - metabolism; Coronaviruses; Cough; COVID-19; COVID-19 - metabolism; COVID-19 - pathology; COVID-19 - virology; Domains; Dyspnea; Envelope protein; Etiology; Fever; Gastrointestinal tract; Health aspects; Host-Pathogen Interactions; Humans; Mechanical ventilation; Medical research; Medicine and health sciences; Pathology; PDZ Domains; Protein Binding; Protein-protein interactions; Proteins; Recombinant Proteins - isolation & purification; Recombinant Proteins - metabolism; Research and Analysis Methods; Respiration; Respiratory diseases; SARS-CoV-2 - isolation & purification; SARS-CoV-2 - metabolism; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Signs and symptoms; Tight Junctions - metabolism; Ventilation; Veterinary colleges; Viral diseases; Viral envelope proteins; Viral proteins; Viruses; Zonula Occludens-1 Protein - metabolism; United States; New York; United States > US; Texas; Pennsylvania
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0251955

Newly emerged SARS-CoV-2 is the cause of an ongoing global pandemic leading to severe respiratory disease in humans. SARS-CoV-2 targets epithelial cells in the respiratory tract and lungs, which can lead to amplified chloride secretion and increased leak across epithelial barriers, contributing to severe pneumonia and consolidation of the lungs as seen in many COVID-19 patients. There is an urgent need for a better understanding of the molecular aspects that contribute to SARS-CoV-2-induced pathogenesis and for the development of approaches to mitigate these damaging pathologies. The multifunctional SARS-CoV-2 Envelope (E) protein contributes to virus assembly/egress, and as a membrane protein, also possesses viroporin channel properties that may contribute to epithelial barrier damage, pathogenesis, and disease severity. The extreme C-terminal (ECT) sequence of E also contains a putative PDZ-domain binding motif (PBM), similar to that identified in the E protein of SARS-CoV-1. Here, we screened an array of GST-PDZ domain fusion proteins using either a biotin-labeled WT or mutant ECT peptide from the SARS-CoV-2 E protein. Notably, we identified a singular specific interaction between the WT E peptide and the second PDZ domain of human Zona Occludens-1 (ZO1), one of the key regulators of TJ formation/integrity in all epithelial tissues. We used homogenous time resolve fluorescence (HTRF) as a second complementary approach to further validate this novel modular E-ZO1 interaction. We postulate that SARS-CoV-2 E interacts with ZO1 in infected epithelial cells, and this interaction may contribute, in part, to tight junction damage and epithelial barrier compromise in these cell layers leading to enhanced virus spread and severe dysfunction that leads to morbidity. Prophylactic/therapeutic intervention targeting this virus-host interaction may effectively reduce airway and/or gastrointestinal barrier damage and mitigate virus spread.