Tight junction protein occludin is an internalization factor for SARS-CoV-2 infection and mediates virus cell-to-cell transmission

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 120; no. 17; p. e2218623120
• Main Authors: Zhang, Jialin, Yang, Wenyu, Roy, Sawrab, Liu, Heidi, Roberts, R Michael, Wang, Liping, Shi, Lei, Ma, Wenjun
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 25-04-2023
• Subjects: Binding; Biological Sciences; Cell fusion; Cell surface; Coronaviruses; COVID-19; Humans; Internalization; Occludin - genetics; Occludin - metabolism; Proteins; Respiratory diseases; SARS-CoV-2 - metabolism; Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - genetics; Strains (organisms); Tight Junction Proteins; Viral diseases; Virus Internalization; Viruses; SARS-CoV-2 variants; internalization; SARS-CoV-2; occludin; cell-to-cell transmission
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2218623120

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads efficiently by spike-mediated, direct cell-to-cell transmission. However, the underlying mechanism is poorly understood. Herein, we demonstrate that the tight junction protein occludin (OCLN) is critical to this process. SARS-CoV-2 infection alters OCLN distribution and expression and causes syncytium formation that leads to viral spread. OCLN knockdown fails to alter SARS-CoV-2 binding but significantly lowers internalization, syncytium formation, and transmission. OCLN overexpression also has no effect on virus binding but enhances virus internalization, cell-to-cell transmission, and replication. OCLN directly interacts with the SARS-CoV-2 spike, and the endosomal entry pathway is involved in OCLN-mediated cell-to-cell fusion rather than in the cell surface entry pathway. All SARS-CoV-2 strains tested (prototypic, alpha, beta, gamma, delta, kappa, and omicron) are dependent on OCLN for cell-to-cell transmission, although the extent of syncytium formation differs between strains. We conclude that SARS-CoV-2 utilizes OCLN as an internalization factor for cell-to-cell transmission.