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

被引:0
作者
Shi, Peidian [1 ,2 ]
Chen, Wenjie [1 ,2 ]
Lyu, Xinxing [1 ,2 ]
Wang, Zhenzhen [1 ,2 ]
Li, Wenchao [1 ,2 ]
Jia, Fengming [1 ,2 ]
Zheng, Chunzhi [1 ,2 ]
Liu, Tingting [1 ,2 ]
Wang, Chuan [1 ,2 ]
Zhang, Yuan [1 ,2 ]
Mi, Zihao [1 ,2 ]
Sun, Yonghu [1 ,2 ]
Chen, Xuechao [1 ,2 ]
Chen, Shengli [1 ,2 ]
Zhou, Guizhi [1 ,2 ]
Liu, Yongxia [1 ,2 ]
Lin, Yingjie [1 ,2 ]
Bai, Fuxiang [1 ,2 ]
Sun, Qing [3 ]
Ogese, Monday O. [4 ]
Yu, Qiang [5 ]
Liu, Jianjun [5 ]
Liu, Hong [1 ,2 ,6 ]
Zhang, Furen [1 ,2 ,6 ,7 ]
机构
[1] Shandong First Med Univ, Hosp Skin Dis, Jinan, Shandong, Peoples R China
[2] Shandong Acad Med Sci, Shandong Prov Inst Dermatol & Venereol, Jinan, Shandong, Peoples R China
[3] Shandong Univ, Qilu Hosp, Dept Dermatol, Jinan, Shandong, Peoples R China
[4] Univ Liverpool, Dept Pharmacol & Therapeut, Liverpool, England
[5] Genome Inst Singapore, Singapore, Singapore
[6] Shandong First Med Univ & Shandong Acad Med Sci, Sch Publ Hlth, Jinan, Shandong, Peoples R China
[7] Shandong Univ Tradit Chinese Med, Jinan, Shandong, Peoples R China
基金
中国国家自然科学基金;
关键词
KAPPA-B ACTIVATION; PATHWAY; DISEASE; FAMILY; RIP; K6;
D O I
10.1038/s41467-024-50481-z
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 x 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-kappa B 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-kappa B 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. Pityriasis rubra pilaris (PRP) is a chronic immune-mediated papulosquamous dermatosis and is caused by dysregulation of keratinocytes. Here the authors identify keratin 32 (KRT32) mutations associated with PRP which results in the inhibitory function of KRT32 towards NF-kB signalling and IKK complex formation being reduced.
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页数:18
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