Plakophilin 1 Suppresses Keratinocyte Innate Immune Responses Through DExD/H Helicases

Plakophilin 1 (PKP1) plays a crucial role in regulating innate immune responses in keratinocytes by sequestering specific dsRNA sensing DExD/H-box RNA helicases, thereby limiting their activation of the MDA5-MAVS signaling axis. This action prevents excessive activation of transcription factors IRF3 and NFκB, reducing the transcription of proinflammatory cytokines like IFN-β1, IL6, and TNFα. Upon dsRNA challenge, PKP1 undergoes proteasomal degradation, releasing the helicases to enable a rapid inflammatory response. PKP1 thus balances epidermal immune homeostasis by providing a barrier against harmful substances and suppressing excessive immune responses, with its loss leading to conditions like ectodermal dysplasia-skin fragility syndrome (EDSFS).