Keratin 16 inhibits type ı interferon responses in differentiating keratinocytes of stressed and diseased skin

Abstract

The stress-induced keratin 16 intermediate filament gene, KRT16 , and K16 protein are spatially restricted to the suprabasal layers of the epidermis and widely used as biomarkers in psoriasis, hidradenitis suppurativa, atopic dermatitis, and other inflammatory disorders. Pathogenic variants in KRT16 cause pachyonychia congenita (PC), a rare genetic condition in which tissue homeostasis is disrupted in palmoplantar epidermis, nail, oral mucosa, and other KRT16 -expressing epithelial appendages. How K16 may regulate the molecular mechanisms underlying these conditions is poorly understood. Here, we show that K16 negatively regulates type I interferon (IFN) signaling and innate immune responses in skin. Clinically, the signature palmoplantar keratoderma lesions in individuals with PC showed enhanced type I IFN signaling. In mouse skin in vivo, loss of Krt16 led to exacerbation of imiquimod-induced psoriasiform disease and heightened recruitment of neutrophils in a phorbol ester–induced model of acute sterile inflammation. In KRT16 -null human keratinocytes, loss of K16 amplified IFN signaling including phosphorylated interferon regulatory factor 7 (IRF7) and interferon-stimulated gene 15 (ISG15) after treatment with synthetic dsRNA poly(I:C). Mechanistically, K16 interacted with effectors of the RIG-I–like receptor (RLR) pathway, including 14-3-3ɛ, and inhibited the 14-3-3ɛ:RIG-I interaction upstream of IFN activation in mouse and immortalized human keratinocytes ex vivo. Topical application of the Janus kinase inhibitor cream ruxolitinib to palmoplantar keratoderma lesions of Krt16 -null mice reduced lesion severity. These findings uncover a previously unrecognized paradigm for keratin-dependent regulation of innate immunity, with implications for our understanding of inflammatory skin diseases and potential treatments for PC.