SARS-CoV-2 spike protein-ACE2 interaction increases carbohydrate sulfotransferases and reduces N-acetylgalactosamine-4-sulfatase by p38 MAPK.

Journal

Signal transduction and targeted therapy

ISSN: 2059-3635

Titre abrégé: Signal Transduct Target Ther

Pays: England

ID NLM: 101676423

Informations de publication

Date de publication:
14 Feb 2024

Historique:

received: 10 07 2023

accepted: 18 12 2023

revised: 04 11 2023

medline: 15 2 2024

pubmed: 15 2 2024

entrez: 14 2 2024

Statut: epublish

Résumé

Immunostaining in lungs of patients who died with COVID-19 infection showed increased intensity and distribution of chondroitin sulfate and decline in N-acetylgalactostamine-4-sulfatase (Arylsulfatase B; ARSB). To explain these findings, human small airway epithelial cells were exposed to the SARS-CoV-2 spike protein receptor binding domain (SPRBD) and transcriptional mechanisms were investigated. Phospho-p38 MAPK and phospho-SMAD3 increased following exposure to the SPRBD, and their inhibition suppressed the promoter activation of the carbohydrate sulfotransferases CHST15 and CHST11, which contributed to chondroitin sulfate biosynthesis. Decline in ARSB was mediated by phospho-38 MAPK-induced N-terminal Rb phosphorylation and an associated increase in Rb-E2F1 binding and decline in E2F1 binding to the ARSB promoter. The increases in chondroitin sulfotransferases were inhibited when treated with phospho-p38-MAPK inhibitors, SMAD3 (SIS3) inhibitors, as well as antihistamine desloratadine and antibiotic monensin. In the mouse model of carrageenan-induced systemic inflammation, increases in phospho-p38 MAPK and expression of CHST15 and CHST11 and declines in DNA-E2F binding and ARSB expression occurred in the lung, similar to the observed effects in this SPRBD model of COVID-19 infection. Since accumulation of chondroitin sulfates is associated with fibrotic lung conditions and diffuse alveolar damage, increased attention to p38-MAPK inhibition may be beneficial in ameliorating Covid-19 infections.

Identifiants

DOI: 10.1038/s41392-024-01741-3 PMID: 38355690

pubmed: 38355690

doi: 10.1038/s41392-024-01741-3

pii: 10.1038/s41392-024-01741-3

doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

Informations de copyright

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