Publikationsdatenbank

Unconventional secretion of unglycosylated ORF8 is critical for the cytokine storm during SARS-CoV-2 infection (2023)

Art

Zeitschriftenartikel / wissenschaftlicher Beitrag

Autoren

Lin, Xiaoyuan (WE 5)

Fu, Beibei

Xiong, Yan

Xing, Na (WE 5)

Xue, Weiwei

Guo, Dong

Zaky, Mohamed

Pavani, Krishna

Kunec, Dusan (WE 5)

Trimpert, Jakob (WE 5)

Wu, Haibo

Quelle

PLoS pathogens

Bandzählung: 19

Heftzählung: 1

Seiten: Artikel e1011128

ISSN: 1553-7374

Sprache

Englisch

Verweise

URL (Volltext): https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1011128

DOI: 10.1371/journal.ppat.1011128

Pubmed: 36689483

Kontakt

Institut für Virologie

Robert-von-Ostertag-Str. 7-13
14163 Berlin
+49 30 838 51833
virologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

Coronavirus disease 2019 is a respiratory infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Evidence on the pathogenesis of SARS-CoV-2 is accumulating rapidly. In addition to structural proteins such as Spike and Envelope, the functional roles of non-structural and accessory proteins in regulating viral life cycle and host immune responses remain to be understood. Here, we show that open reading frame 8 (ORF8) acts as messenger for inter-cellular communication between alveolar epithelial cells and macrophages during SARS-CoV-2 infection. Mechanistically, ORF8 is a secretory protein that can be secreted by infected epithelial cells via both conventional and unconventional secretory pathways. Conventionally secreted ORF8 is glycosylated and loses the ability to recognize interleukin 17 receptor A of macrophages, possibly due to the steric hindrance imposed by N-glycosylation at Asn78. However, unconventionally secreted ORF8 does not undergo glycosylation without experiencing the ER-Golgi trafficking, thereby activating the downstream NF-κB signaling pathway and facilitating a burst of cytokine release. Furthermore, we show that ORF8 deletion in SARS-CoV-2 attenuates inflammation and yields less lung lesions in hamsters. Our data collectively highlights a role of ORF8 protein in the development of cytokine storms during SARS-CoV-2 infection.