Keratin 16 spatially inhibits type I interferon responses in stressed and diseased skin

Abstract The stress-induced keratin 16 is broadly used as a biomarker in inflammatory skin disorders while pathogenic variants in KRT16 cause pachyonychia congenita (PC), a condition in which differentiation and homeostasis are disrupted in palmoplantar epidermis and epithelial appendages. How K16 impacts these disorders at a molecular level is poorly understood. Here we report that K16 spatially restricts type I interferon (IFN) signaling and innate immunity in palmoplantar keratoderma (PPK) lesions in PC patients, imiquimod- and phorbol ester-induced models of sterile inflammation in mouse skin, and poly(I:C)-treated human keratinocytes ex vivo. Mechanistically, K16 interacts with effectors of the RIG-I-like receptor (RLR) pathway, including 14-3-3ɛ, and inhibits the 14-3-3ɛ:RIG-I interaction upstream of IFN activation. Topical application of the JAK inhibitor Ruxolitinib reduces the severity of PC-PPK-like lesions in Krt16 null mice. These findings uncover a new paradigm for keratin-dependent regulation of innate immunity and suggest a new approach to PC treatment. One sentence summary KRT16 negatively regulates type I interferon signaling and innate immune responses in the skin, offering insight into the pathophysiology of inflammatory skin diseases including pachyonychia congenita, psoriasis and others. Competing Interest Statement The authors have declared no competing interest. Footnotes This is a revised version of a manuscript that is under consideration for publication in a scientific journal involving peer-review.