Hipk Is a Critical Mediator of Stress-Induced Intestinal Hyperplasia via the Hippo Pathway in Drosophila

The Drosophila midgut serves as a powerful model system for studying the mechanisms underlying stem cell hyperproliferation induced by gut damage and Yorkie (Yki) activation. Homeodomain-interacting protein kinase (Hipk) has recently been shown to regulate intestinal stem cell (ISC) proliferation and differentiation during normal homeostasis. Here, we show that Hipk is cell-autonomously required for ISC hyperproliferation stimulated by both gut damage and Yki activation. Progenitor-specific hipk knockdown abolished the ISC hyperproliferation and gut hyperplasia induced by dextran sulfate sodium (DSS)-mediated injury and Yki overexpression. Mechanistically, Hipk promotes Yki protein stability and nuclear accumulation in progenitors. This regulation is specific to wild-type Yki, as the constitutively active YkiS168A mutant, which escapes Warts-mediated inhibition, is insensitive to Hipk depletion. These findings identify Hipk as a critical regulator of Yki activation during ISC hyperproliferation.