| Title: |
The Hippo terminal effector YAP boosts enterovirus replication in type 1 diabetes |
| Authors: |
Geravandi, Shirin; Liu, Huan; Pahwa, Heena; Madduri, Murali Krishna; Atawneh, Farah; Miraki Feriz, Adib; Rafizadeh, Sahar; Kruf, Annabelle Elisabeth; Khazaei, Mona; Bahrami, Pouria; Gotti, David; Elawour, Mohamed; Elgamal, Ruth M.; Grasso, Ausilia Maria; Bund, David; Lupse, Blaz; Azizi, Zahra; Zabad, Omar; Bouzakri, Karim; Horwitz, Marc; Pugliese, Alberto; Maedler, Kathrin; Ardestani, Amin |
| Publisher Information: |
Nature Publishing Group |
| Publication Year: |
2025 |
| Collection: |
University of Hull: Repository@Hull |
| Subject Terms: |
Autoimmune diseases; Infection; Stress signalling; Type 1 diabetes |
| Description: |
Type 1 diabetes (T1D) risk has been associated with enteroviral infections, particularly coxsackieviruses B (CVB). Cellular host factors contributing to virus-induced islet autoimmunity remain unclear. We show that the Hippo pathway effector Yes-associated Protein (YAP) is markedly upregulated in the exocrine and endocrine pancreas of T1D and at-risk autoantibody-positive (AAb+) donors, along with its target CTGF. YAP expression correlates with CVB RNA presence, often in or near infected cells. YAP overexpression enhances CVB replication, islet inflammation, and β-cell apoptosis, whereas its inhibition halts viral replication in primary and immortalized pancreatic cells. In exocrine-islet co-cultures, CVB triggers YAP and target gene expression. In mice, chronic β-cell YAP expression impairs glucose tolerance, abolishes insulin secretion, and promotes β-cell dedifferentiation. Mechanistically, YAP, in complex with its transcription factor TEAD, induces its own negative regulator MST1. MST1 inhibition boosts viral replication and reduces β-cell apoptosis, constituting a negative feedback loop in which the reciprocal antagonism between YAP and MST1 balances viral replication and β-cell death during CVB infections. YAP is thus an important host factor for enteroviral amplification, offering a potential antiviral target in T1D. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
https://hull-repository.worktribe.com/output/5429374; Nature Communications; Volume 16; Issue 1 |
| DOI: |
10.1038/s41467-025-64508-6 |
| Availability: |
https://hull-repository.worktribe.com/file/5429374/1/Published%20article; https://hull-repository.worktribe.com/output/5429374; https://doi.org/10.1038/s41467-025-64508-6 |
| Rights: |
openAccess ; http://creativecommons.org/licenses/by/4.0 |
| Accession Number: |
edsbas.33F7591A |
| Database: |
BASE |