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.
Show 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.
Matching journals
The top 7 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Immune dysregulation in SHARPIN-deficient mice is dependent on CYLD-mediated cell death 96%
- Histone H3K27me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism 95%
- MDA5 ISGylation is crucial for immune signaling to control viral replication and pathogenesis 94%
Similar papers in this journal
- Targeting SERCA2 in organotypic epidermis reveals MEK inhibition as a therapeutic strategy for Darier disease. 97%
- ERK hyperactivation in epidermal keratinocytes impairs intercellular adhesion and drives Grover disease pathology 95%
- Flotillin-2 dampens T cell antigen-sensitivity and functionality 94%
Similar papers in this journal
- UBE2N is essential for maintenance of skin homeostasis and suppression of inflammation 96%
- Cutaneous lupus features specialized stromal niches and altered retroelement expression 96%
- T cells promote distinct transcriptional programs of cutaneous inflammatory disease in keratinocytes and dermal fibroblasts 95%
Similar papers in this journal
- Xenogeneic Skin Transplantation Promotes Angiogenesis and Tissue Regeneration Through Vitamin D-Activated Trem2+ Macrophages 94%
- Selective disruption of lipid peroxide homeostasis in intratumoral regulatory T cells by targeting FSP1 enhances cancer immunity 94%
- HIRA loss transforms FH-deficient cells 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.