Cet article est une Preprint
Les preprints sont des rapports de recherche préliminaires qui n'ont pas été certifiés par l’évaluation par les pairs. Ils ne devraient pas être considérés comme guidant la pratique clinique ou les comportements liés à la santé et ne devraient pas être rapportés dans les médias comme des informations établies.
Les preprints publiées en ligne permettent aux auteurs de recevoir des commentaires rapidement, et toute la communauté scientifique peut évaluer indépendamment le travail et répondre en conséquence. Ces commentaires sont publiés avec les preprints que quiconque peut lire et servir d’évaluation post-publication.
Human coronaviruses activate and hijack the proteostasis guardian HSF1 to enhance viral replication (preprint)
biorxiv; 2022.
Preprint
Dans Anglais
| bioRxiv | ID: ppzbmed-10.1101.2022.12.22.519205
ABSTRACT
Organisms respond to proteotoxic stress by activating a cellular defense mechanism, known as the heat shock response (HSR), that triggers the expression of cytoprotective heat shock proteins (HSP) to counteract the damaging effects of proteostasis disruption. The HSR is regulated by a family of transcription factors (heat shock factors, HSFs); among six human HSFs, HSF1 acts as a proteostasis guardian regulating acute and severe stress-driven transcriptional responses. Seasonal coronaviruses HCoV-229E, HCoV-NL63, HCoV-OC43 and HCoV-HKU1 (sHCoV) are globally circulating in the human population. Although sHCoV generally cause only mild upper respiratory diseases in immunocompetent hosts, severe complications may occur in specific populations. There is no effective treatment for sHCoV infections, also due to the limited knowledge on sHCoV biology. We now show that both Alpha- and Beta- sHCoV are potent inducers of HSF1, selectively promoting HSF1 phosphorylation at serine-326 residue and nuclear translocation, and triggering a powerful HSF1-driven transcriptional response in infected cells at late stages of infection. Despite the coronavirus-mediated shut-down of the host cell translational machinery, high levels of selected canonical and non-canonical HSF1-target genes products, including HSP70, HSPA6 and the zinc-finger AN1-type domain-2a gene/AIRAP, were found in HCoV-infected cells. Interestingly, silencing experiments demonstrate that HSR activation does not merely reflect a cellular defense response to viral infection, but that sHCoV activate and hijack the HSF1-pathway for their own gain. Notably, nuclear HSF1 pools depletion via Direct-Targeted HSF1 inhibitor (DTHIB) treatment was highly effective in hindering sHCoV replication in lung cells. Altogether the results open new scenarios for the search of innovative antiviral strategies in the treatment of coronavirus infections.
Texte intégral:
Disponible
Collection:
Preprints
Base de données:
bioRxiv
Sujet Principal:
Infections de l'appareil respiratoire
/
Maladies virales
/
Fractures de fatigue
/
Infections à coronavirus
/
Infections à Coronaviridae
/
Troubles de l'homéostasie des protéines
/
Infections
langue:
Anglais
Année:
2022
Type de document:
Preprint
Documents relatifs à ce sujet
MEDLINE
...
LILACS
LIS