Keratin 16 spatially inhibits type I interferon responses in stressed skin

Cohen, E.; Xu, Y.; Orosco, A.; Wang, D.; Johnson, C. N.; Steen, K.; Sarkar, M. K.; Ozlu, N.; Tsoi, L. C.; Gudsonsson, J. E.; Parent, C.; Coulombe, P. A.

doi:10.1101/2024.12.27.630544

bioRxiv · 10.1101/2024.12.27.630544

Keratin 16 spatially inhibits type I interferon responses in stressed skin

Cohen, E.·Xu, Y.·Orosco, A.·Wang, D.·Johnson, C. N.·Steen, K.·Sarkar, M. K.·Ozlu, N.·Tsoi, L. C.·Gudsonsson, J. E.·Parent, C.·Coulombe, P. A.

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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 14-3-3{varepsilon}, and inhibits the 14-3-3{varepsilon}: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 summaryKRT16 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.

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Cohen, E., Xu, Y., Orosco, A., Wang, D., Johnson, C. N., Steen, K., Sarkar, M. K., Ozlu, N., Tsoi, L. C., Gudsonsson, J. E., Parent, C., Coulombe, P. A.. 2024-12-28. Keratin 16 spatially inhibits type I interferon responses in stressed skin. https://doi.org/10.1101/2024.12.27.630544

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