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

Peidian Shi, Wenjie Chen, Xinxing Lyu, Zhenzhen Wang, Wenchao Li, Fengming Jia, Chunzhi Zheng, Tingting Liu, Chuan Wang, Yuan Zhang, Zihao Mi, Yonghu Sun, Xuechao Chen, Shengli Chen, Guizhi Zhou, Yongxia Liu, Yingjie Lin, Fuxiang Bai, Qing Sun, Monday O. Ogese, Qiang Yu, Jianjun Liu, Hong Liu () and Furen Zhang ()
Additional contact information
Peidian Shi: Shandong First Medical University
Wenjie Chen: Shandong First Medical University
Xinxing Lyu: Shandong First Medical University
Zhenzhen Wang: Shandong First Medical University
Wenchao Li: Shandong First Medical University
Fengming Jia: Shandong First Medical University
Chunzhi Zheng: Shandong First Medical University
Tingting Liu: Shandong First Medical University
Chuan Wang: Shandong First Medical University
Yuan Zhang: Shandong First Medical University
Zihao Mi: Shandong First Medical University
Yonghu Sun: Shandong First Medical University
Xuechao Chen: Shandong First Medical University
Shengli Chen: Shandong First Medical University
Guizhi Zhou: Shandong First Medical University
Yongxia Liu: Shandong First Medical University
Yingjie Lin: Shandong First Medical University
Fuxiang Bai: Shandong First Medical University
Qing Sun: Shandong University
Monday O. Ogese: University of Liverpool
Qiang Yu: Genome Institute of Singapore
Jianjun Liu: Genome Institute of Singapore
Hong Liu: Shandong First Medical University
Furen Zhang: Shandong First Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-50481-z Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50481-z

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-50481-z

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().