SPT6 maintains epidermal homeostasis by inhibiting an NF-κB-positive feedback loop to prevent excessive inflammation

This study investigates the role of SPT6, a transcription elongation factor, in maintaining epidermal and immune homeostasis using a conditional knockout mouse model. The loss of SPT6 in basal keratinocytes resulted in psoriasis-like skin inflammation, characterized by epidermal hyperplasia, immune cell infiltration, parakeratosis, and hyperkeratosis, along with delayed wound healing and impaired Wnt signaling. Single-cell RNA sequencing identified keratinocyte subpopulations with inflammatory signatures and elevated NF-κB signaling. SPT6 was found to suppress NF-κB signaling by binding to an enhancer of the RELA gene, preventing its positive transcriptional feedback loop. The study concludes that SPT6 is crucial for suppressing inflammation and maintaining epidermal homeostasis, suggesting that the skin's default state may be primed for inflammation without active suppression by factors like SPT6.