ZNF750 Loss of Function Drives Spontaneous Psoriasiform Skin Inflammation

Epidermal keratinocytes are not only crucial for maintaining skin barrier physical functions but also play various roles in the initiation, progression, and maintenance phases of skin inflammation. ZNF750 is an epithelial-specific transcription factor expressed in differentiating keratinocytes, whose activity is required for keratinocyte terminal differentiation. In humans, ZNF750 sequence variant causes psoriasis-like skin disease. In this study, using a genetic mouse model to study the role played by ZNF750 in epidermal homeostasis, we reveal that ZNF750 activity is essential for preventing skin inflammation. We show that a loss of ZNF750 activity results in the rapid development of psoriasiform skin lesions. Molecular dissection further demonstrated an impaired balance between epidermal cell proliferation and differentiation, induction of proinflammatory factors by Znf750-deficient keratinocytes, and a massive immune cell infiltration. Altogether, our study highlights the importance of keratinocytes in inflammatory skin disease pathogenesis, demonstrating ZNF750 loss-of-function sufficiency in driving severe psoriasiform skin inflammation, which resembles the diseased human condition in patients with pathogenic ZNF750 sequence variants.