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

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.