Keratin 16 spatially inhibits type I interferon responses in stressed skin: Implications for pachyonychia congenita and chronic inflammatory skin diseases

Abstract

Expression of the stress-induced keratin intermediate filament gene KRT16 (protein K16) is spatially restricted to the suprabasal compartment of the epidermis and extensively used as a biomarker for psoriasis, hidradenitis suppurativa and other inflammatory disorders. Pathogenic variants in KRT16 lead to pachyonychia congenita (PC), a rare genetic skin condition in which tissue homeostasis is disrupted in palmoplantar epidermis, oral mucosa, and other epithelial appendages. Despite its importance, the role of K16 in these conditions is not well understood. Here, we report that K16 negatively regulates type-I interferon (IFN) signaling and innate immune responses. In vivo studies in mouse skin show that the absence of Krt16 exacerbates imiquimod-induced psoriasiform disease and enhances neutrophil recruitment in a phorbol ester-induced model of sterile inflammation. In KRT16-null NTERT human keratinocytes in culture, the absence of K16 amplifies IFN response to synthetic dsRNA poly(I:C), including increased levels of phospho-IRF7 and ISG15. Mechanistically, K16 interacts with RIG-I-like receptor (RLR) pathway effectors, such as 14-3-3epsilon, and disrupts the 14-3-3epsilon:RIG-I interaction, thereby downregulating IFN activation. Of interest, transcriptomic data from PC patients and PPK-like lesions in Krt16 mouse footpad skin show upregulation of IFN and dsRNA effectors. These findings uncover a new paradigm for keratin-dependent regulation of innate immunity, with clear implications for the pathophysiology of PC and chronic inflammatory diseases.