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) characterized by skin fragility, chronic inflammation, and recurrent infections. Here, we show that PKP1, extending its role in barrier formation, is a critical regulator of innate immune responses. Mechanistically, PKP1 sequesters a subset of dsRNA sensing DExD/H-box RNA helicases - DDX1, DDX3X, DDX21, and DHX15 - thereby limiting their availability for activation of the MDA5-MAVS signaling axis. The inactivation of the helicases by PKP1 prevents excessive activation of transcription factors IRF3 and NFκB, thus dampening the transcription of proinflammatory cytokines including IFN-β1, IL6, and TNFα. Activation of the innate immune response by a dsRNA challenge induces the proteasomal degradation of PKP1. This releases the helicases and enables dsRNA sensing and a rapid inflammatory response. Thus, upon an acute provocation, keratinocytes circumvent the repressive effect by reducing the PKP1 level, whereas steady state levels limit the inflammatory reaction to avoid exaggerated inflammation as observed upon the general loss of PKP1 in EDSFS. In summary, PKP1 combines two complementary functions essential for epidermal immune homeostasis: it provides a barrier to prevent the entry of harmful substances and it suppresses innate immune responses in keratinocytes.