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, Blaž Lupše, Zahra Azizi, Omar Zabad, Karim Bouzakri, Marc S. Horwitz, Alberto Pugliese, Kathrin Maedler, Amin Ardestani
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.