Plakophilin 1 suppresses keratinocyte innate immune responses through DExD/H helicases

The innate immune response is a first line of defense that allows a rapid reaction to pathogens as well as molecules released from damaged cells. It relies on pathogen-sensing receptors, many of which are nucleic acid-binding proteins, including RNA helicases. Plakophilin 1 (PKP1) is a desmosomal protein essential for strong intercellular adhesion and epithelial barrier integrity. Loss-of-function mutations in PKP1 cause ectodermal dysplasia-skin fragility syndrome (EDSFS), which is characterized by skin fragility, chronic inflammation, and recurrent infections. Here, we report that PKP1, whose role in barrier formation is to function as a critical regulator of innate immune responses. PKP1 sequesters a subset of dsRNAs that sense DExD/H-box RNA helicases-DDX1, DDX3X, DDX21, and DHX15. This limits their ability to activate the MDA5-MAVS signaling axis and prevents excessive activation of IRF3- and NFκB-driven gene expression, including the synthesis of proinflammatory cytokines, mainly IFN-β1, IL6, and TNFα. The inhibitory role of PKP1 is erased during innate immune responses by dsRNA cues, inducing proteasomal PKP1 degradation. This releases sequestered helicases, enabling dsRNA sensing and a rapid inflammatory response. Collectively, these findings identify PKP1 as a key gatekeeper that prevents exaggerated inflammation in quiescent keratinocytes, which is supported by excessive inflammation in EDSFS upon PKP1 loss. In healthy keratinocytes with proinflammatory traits, PKP1 is rapidly degraded, allowing the activation of the MDA5-MAVS signaling cascade by helicases to initiate inflammation. Hence, PKP1 combines two complementary functions essential for epidermal immune homeostasis: it provides a physical barrier preventing substance entry and suppresses innate immune responses in keratinocytes.