Loss-of-function mutations in Keratin 32 gene disrupt skin immune homeostasis in pityriasis rubra pilaris.

Autor: Shi P; Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China.; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China., Chen W; Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China.; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China., Lyu X; Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China.; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China., Wang Z; Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China.; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China., Li W; Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China.; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China., Jia F; Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China.; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China., Zheng C; Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China.; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China., Liu T; Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China.; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China., Wang C; Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China.; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China., Zhang Y; Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China.; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China., Mi Z; Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China.; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China., Sun Y; Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China.; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China., Chen X; Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China.; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China., Chen S; Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China.; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China., Zhou G; Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China.; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China., Liu Y; Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China.; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China., Lin Y; Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China.; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China., Bai F; Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China.; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China., Sun Q; Department of Dermatology, Qilu Hospital, Shandong University, Jinan, Shandong, China., Ogese MO; Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK., Yu Q; Genome Institute of Singapore, Singapore, Singapore., Liu J; Genome Institute of Singapore, Singapore, Singapore., Liu H; Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China. hongyue2519@hotmail.com.; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China. hongyue2519@hotmail.com.; School of Public Health, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China. hongyue2519@hotmail.com., Zhang F; Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China. zhangfuren@hotmail.com.; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China. zhangfuren@hotmail.com.; School of Public Health, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China. zhangfuren@hotmail.com.; Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China. zhangfuren@hotmail.com.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jul 24; Vol. 15 (1), pp. 6259. Date of Electronic Publication: 2024 Jul 24.
DOI: 10.1038/s41467-024-50481-z
Abstrakt: Pityriasis rubra pilaris (PRP) is an inflammatory papulosquamous dermatosis, characterized by hyperkeratotic follicular papules and erythematous desquamative plaques. The precise pathogenic mechanism underlying PRP remains incompletely understood. Herein, we conduct a case-control study involving a cohort of 102 patients with sporadic PRP and 800 healthy controls of Han Chinese population and identify significant associations (P = 1.73 × 10 -6 ) between PRP and heterozygous mutations in the Keratin 32 gene (KRT32). KRT32 is found to be predominantly localized in basal keratinocytes and exhibits an inhibitory effect on skin inflammation by antagonizing the NF-κB pathway. Mechanistically, KRT32 binds to NEMO, promoting excessive K48-linked polyubiquitination and NEMO degradation, which hinders IKK complex formation. Conversely, loss-of-function mutations in KRT32 among PRP patients result in NF-κB hyperactivation. Importantly, Krt32 knockout mice exhibit a PRP-like dermatitis phenotype, suggesting compromised anti-inflammatory function of keratinocytes in response to external pro-inflammatory stimuli. This study proposes a role for KRT32 in regulating inflammatory immune responses, with damaging variants in KRT32 being an important driver in PRP development. These findings offer insights into the regulation of skin immune homeostasis by keratin and open up the possibility of using KRT32 as a therapeutic target for PRP.
(© 2024. The Author(s).)
Databáze: MEDLINE
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