The Hippo terminal effector YAP boosts enterovirus replication in type 1 diabetes

Shirin Geravandi, Huan Liu, Heena Pahwa, Murali Krishna Madduri, Farah Atawneh, Adib Miraki Feriz, Sahar Rafizadeh, Annabelle Elisabeth Kruf, Mona Khazaei, Pouria Bahrami, David Gotti, Mohamed Elawour, Ruth M. Elgamal, Ausilia Maria Grasso, David Bund, Blaz Lupse, Zahra Azizi, Omar Zabad, Karim Bouzakri, Marc Horwitz, Alberto Pugliese, Kathrin Maedler () and Amin Ardestani ()
Additional contact information
Shirin Geravandi: University of Bremen, Islet Biology Laboratory, Centre for Biomolecular Interactions Bremen
Huan Liu: University of Bremen, Islet Biology Laboratory, Centre for Biomolecular Interactions Bremen
Heena Pahwa: University of Bremen, Islet Biology Laboratory, Centre for Biomolecular Interactions Bremen
Murali Krishna Madduri: University of Bremen, Islet Biology Laboratory, Centre for Biomolecular Interactions Bremen
Farah Atawneh: University of Bremen, Islet Biology Laboratory, Centre for Biomolecular Interactions Bremen
Adib Miraki Feriz: Wellcome Genome Campus
Sahar Rafizadeh: University of Bremen, Islet Biology Laboratory, Centre for Biomolecular Interactions Bremen
Annabelle Elisabeth Kruf: University of Bremen, Islet Biology Laboratory, Centre for Biomolecular Interactions Bremen
Mona Khazaei: University of Bremen, Islet Biology Laboratory, Centre for Biomolecular Interactions Bremen
Pouria Bahrami: University of Bremen, Islet Biology Laboratory, Centre for Biomolecular Interactions Bremen
David Gotti: University of Bremen, Islet Biology Laboratory, Centre for Biomolecular Interactions Bremen
Mohamed Elawour: University of Bremen, Islet Biology Laboratory, Centre for Biomolecular Interactions Bremen
Ruth M. Elgamal: San Diego
Ausilia Maria Grasso: University of Bremen, Islet Biology Laboratory, Centre for Biomolecular Interactions Bremen
David Bund: University of Bremen, Islet Biology Laboratory, Centre for Biomolecular Interactions Bremen
Blaz Lupse: University of Bremen, Islet Biology Laboratory, Centre for Biomolecular Interactions Bremen
Zahra Azizi: University of Bremen, Islet Biology Laboratory, Centre for Biomolecular Interactions Bremen
Omar Zabad: University of Bremen, Islet Biology Laboratory, Centre for Biomolecular Interactions Bremen
Karim Bouzakri: Fédération de Médecine Translationnelle de Strasbourg
Marc Horwitz: University of British Columbia Vancouver
Alberto Pugliese: Division of Endocrinology and Metabolism
Kathrin Maedler: University of Bremen, Islet Biology Laboratory, Centre for Biomolecular Interactions Bremen
Amin Ardestani: University of Bremen, Islet Biology Laboratory, Centre for Biomolecular Interactions Bremen

Nature Communications, 2025, vol. 16, issue 1, 1-26

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-64508-6

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