ADAM17 variant causes hair loss via ubiquitin ligase TRIM47–mediated degradation
Xiaoxiao Wang, Chaolan Pan, Luyao Zheng, Jianbo Wang, Quan Zou, Peiyi Sun, Kaili Zhou, Anqi Zhao, Qiaoyu Cao, Wei He, Yumeng Wang, Ruhong Cheng, Zhirong Yao, Si Zhang, Hui Zhang, Ming Li
Xiaoxiao Wang, Chaolan Pan, Luyao Zheng, Jianbo Wang, Quan Zou, Peiyi Sun, Kaili Zhou, Anqi Zhao, Qiaoyu Cao, Wei He, Yumeng Wang, Ruhong Cheng, Zhirong Yao, Si Zhang, Hui Zhang, Ming Li
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Research Article Dermatology Genetics

ADAM17 variant causes hair loss via ubiquitin ligase TRIM47–mediated degradation

Abstract

Hypotrichosis is a genetic disorder characterized by a diffuse and progressive loss of scalp and/or body hair. Nonetheless, the causative genes for several affected individuals remain elusive, and the underlying mechanisms have yet to be fully elucidated. Here, we discovered a dominant variant in a disintegrin and a metalloproteinase domain 17 (ADAM17) gene caused hypotrichosis with woolly hair. Adam17 (p.D647N) knockin mice mimicked the hair abnormality in patients. ADAM17 (p.D647N) mutation led to hair follicle stem cell (HFSC) exhaustion and caused abnormal hair follicles, ultimately resulting in alopecia. Mechanistic studies revealed that ADAM17 binds directly to E3 ubiquitin ligase tripartite motif-containing protein 47 (TRIM47). ADAM17 variant enhanced the association between ADAM17 and TRIM47, leading to an increase in ubiquitination and subsequent degradation of ADAM17 protein. Furthermore, reduced ADAM17 protein expression affected the Notch signaling pathway, impairing the activation, proliferation, and differentiation of HFSCs during hair follicle regeneration. Overexpression of Notch intracellular domain rescued the reduced proliferation ability caused by Adam17 variant in primary fibroblast cells.

Authors

Xiaoxiao Wang, Chaolan Pan, Luyao Zheng, Jianbo Wang, Quan Zou, Peiyi Sun, Kaili Zhou, Anqi Zhao, Qiaoyu Cao, Wei He, Yumeng Wang, Ruhong Cheng, Zhirong Yao, Si Zhang, Hui Zhang, Ming Li

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Figure 7

ADAM17 (p.D647N) variant affects Notch signaling, resulting in hair follicle malformation.

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ADAM17 (p.D647N) variant affects Notch signaling, resulting in hair fol...
(A) Effects of ADAM17 mutation on protein levels of key molecules involved in Notch signaling observed in the skin biopsy of the patient. (B) Adam17 mutation inhibited Notch signaling in the skin tissues of mice. (C) Effects of Adam17 mutation on mRNA levels of key molecules involved in Notch signaling observed in the skin tissues of mice. (n = 6 biological replicates.) (D) Immunohistochemical staining showed that Adam17 mutation led to downregulation of ADAM17 and Notch intracellular domain (NICD) expression but not full-length Notch1 in Adam17D647N/D647N mice. Scale bar, 250 μm. (E) Immunofluorescence showed that Adam17 mutation led to downregulation of ADAM17 and NICD expression in hair follicle of Adam17D647N/D647N mice. Scale bar, 80 μm. (F) Cellular component separation assay showed that NICD protein level was decreased in nucleus of ADAM17-mutant HaCaT cells. Lamin B2 and α-tubulin were used as the nuclear (Nue) and cytosolic (Cyto) protein makers, respectively. (G and H) Overexpressing NICD significantly rescued the proliferation activity of primary fibroblasts derived from Adam17D647N/D647N mice. (n = 3 biological replicates.) (I) Schematic diagram of Notch signaling pathway. Following sequentially cleaving by ADAM10 and γ-secretase, Notch released its NICD. NICD then translocated to nucleus, and, in collaboration with RBPJ and Mastermind, activated the transcription of target genes, including members of the Hes and Hey families. All experiments were repeated 3 times. Results were expressed as mean ± SD; *P < 0.05; **P < 0.01; ***P < 0.001; 1-way ANOVA and Kruskal-Wallis test (C); Brown-Forsythe and Welch ANOVA tests (G).