Unconventional secretion of unglycosylated ORF8 is critical for the cytokine storm during SARS-CoV-2 infection.
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-stru...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-01-01
|
| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011128&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832582969681772544 |
|---|---|
| author | Xiaoyuan Lin Beibei Fu Yan Xiong Na Xing Weiwei Xue Dong Guo Mohamed Zaky Krishna Pavani Dusan Kunec Jakob Trimpert Haibo Wu |
| author_facet | Xiaoyuan Lin Beibei Fu Yan Xiong Na Xing Weiwei Xue Dong Guo Mohamed Zaky Krishna Pavani Dusan Kunec Jakob Trimpert Haibo Wu |
| author_sort | Xiaoyuan Lin |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-b03a30e100fd4734b337c866d9d97390 |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2023-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-b03a30e100fd4734b337c866d9d973902025-01-29T05:30:38ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742023-01-01191e101112810.1371/journal.ppat.1011128Unconventional secretion of unglycosylated ORF8 is critical for the cytokine storm during SARS-CoV-2 infection.Xiaoyuan LinBeibei FuYan XiongNa XingWeiwei XueDong GuoMohamed ZakyKrishna PavaniDusan KunecJakob TrimpertHaibo WuCoronavirus 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.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011128&type=printable |
| spellingShingle | Xiaoyuan Lin Beibei Fu Yan Xiong Na Xing Weiwei Xue Dong Guo Mohamed Zaky Krishna Pavani Dusan Kunec Jakob Trimpert Haibo Wu Unconventional secretion of unglycosylated ORF8 is critical for the cytokine storm during SARS-CoV-2 infection. PLoS Pathogens |
| title | Unconventional secretion of unglycosylated ORF8 is critical for the cytokine storm during SARS-CoV-2 infection. |
| title_full | Unconventional secretion of unglycosylated ORF8 is critical for the cytokine storm during SARS-CoV-2 infection. |
| title_fullStr | Unconventional secretion of unglycosylated ORF8 is critical for the cytokine storm during SARS-CoV-2 infection. |
| title_full_unstemmed | Unconventional secretion of unglycosylated ORF8 is critical for the cytokine storm during SARS-CoV-2 infection. |
| title_short | Unconventional secretion of unglycosylated ORF8 is critical for the cytokine storm during SARS-CoV-2 infection. |
| title_sort | unconventional secretion of unglycosylated orf8 is critical for the cytokine storm during sars cov 2 infection |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011128&type=printable |
| work_keys_str_mv | AT xiaoyuanlin unconventionalsecretionofunglycosylatedorf8iscriticalforthecytokinestormduringsarscov2infection AT beibeifu unconventionalsecretionofunglycosylatedorf8iscriticalforthecytokinestormduringsarscov2infection AT yanxiong unconventionalsecretionofunglycosylatedorf8iscriticalforthecytokinestormduringsarscov2infection AT naxing unconventionalsecretionofunglycosylatedorf8iscriticalforthecytokinestormduringsarscov2infection AT weiweixue unconventionalsecretionofunglycosylatedorf8iscriticalforthecytokinestormduringsarscov2infection AT dongguo unconventionalsecretionofunglycosylatedorf8iscriticalforthecytokinestormduringsarscov2infection AT mohamedzaky unconventionalsecretionofunglycosylatedorf8iscriticalforthecytokinestormduringsarscov2infection AT krishnapavani unconventionalsecretionofunglycosylatedorf8iscriticalforthecytokinestormduringsarscov2infection AT dusankunec unconventionalsecretionofunglycosylatedorf8iscriticalforthecytokinestormduringsarscov2infection AT jakobtrimpert unconventionalsecretionofunglycosylatedorf8iscriticalforthecytokinestormduringsarscov2infection AT haibowu unconventionalsecretionofunglycosylatedorf8iscriticalforthecytokinestormduringsarscov2infection |