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ADAM17 变异通过泛素连接酶 TRIM47 介导的降解导致脱发。

ADAM17 variant causes hair loss via ubiquitin ligase TRIM47-mediated degradation.

机构信息

Department of Dermatology, Xinhua Hospital, and.

Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China.

出版信息

JCI Insight. 2024 May 21;9(13):e177588. doi: 10.1172/jci.insight.177588.

DOI:10.1172/jci.insight.177588
PMID:38771644
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11383180/
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.

摘要

毛发稀少症是一种以头皮和/或体毛弥漫性和进行性缺失为特征的遗传疾病。然而，一些受影响个体的致病基因仍然难以捉摸，其潜在机制仍未完全阐明。在这里，我们发现一个离散金属蛋白酶域 17（ADAM17）基因中的显性变异导致具有羊毛状毛发的毛发稀少症。Adam17（p.D647N）基因敲入小鼠模拟了患者的毛发异常。ADAM17（p.D647N）突变导致毛囊干细胞（HFSC）衰竭，并导致异常的毛囊，最终导致脱发。机制研究表明，ADAM17 直接与含有三肽重复结构域的 E3 泛素连接酶 47（TRIM47）结合。ADAM17 变体增强了 ADAM17 和 TRIM47 之间的关联，导致 ADAM17 蛋白的泛素化和随后的降解增加。此外，ADAM17 蛋白表达的减少影响 Notch 信号通路，损害毛囊再生过程中 HFSCs 的激活、增殖和分化。Notch 细胞内结构域的过表达挽救了 Adam17 变体在原代成纤维细胞中引起的增殖能力降低。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcff/11383180/4d53ce9bf3c8/jciinsight-9-177588-g035.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcff/11383180/dd1c20bfe18c/jciinsight-9-177588-g029.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcff/11383180/44f95555dabd/jciinsight-9-177588-g030.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcff/11383180/953e96bcbc06/jciinsight-9-177588-g031.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcff/11383180/c84d68049a0d/jciinsight-9-177588-g032.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcff/11383180/7f389ddaa336/jciinsight-9-177588-g033.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcff/11383180/e4f1eaf42967/jciinsight-9-177588-g034.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcff/11383180/4d53ce9bf3c8/jciinsight-9-177588-g035.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcff/11383180/dd1c20bfe18c/jciinsight-9-177588-g029.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcff/11383180/44f95555dabd/jciinsight-9-177588-g030.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcff/11383180/953e96bcbc06/jciinsight-9-177588-g031.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcff/11383180/c84d68049a0d/jciinsight-9-177588-g032.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcff/11383180/7f389ddaa336/jciinsight-9-177588-g033.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcff/11383180/e4f1eaf42967/jciinsight-9-177588-g034.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcff/11383180/4d53ce9bf3c8/jciinsight-9-177588-g035.jpg

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本文引用的文献

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J Cell Biol. 2024 May 6;223(5). doi: 10.1083/jcb.202211041. Epub 2024 Feb 15.
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FGFR2 mutations promote endometrial cancer progression through dual engagement of EGFR and Notch signalling pathways.FGFR2 突变通过双重结合 EGFR 和 Notch 信号通路促进子宫内膜癌的进展。
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Quality of life in children and adolescents with alopecia areata-A systematic review.
斑秃儿童和青少年的生活质量——一项系统综述
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The Role of ADAM17 in Inflammation-Related Atherosclerosis.ADAM17 在炎症相关动脉粥样硬化中的作用。
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TRIM47 is a novel endothelial activation factor that aggravates lipopolysaccharide-induced acute lung injury in mice via K63-linked ubiquitination of TRAF2.TRIM47 是一种新型的内皮激活因子，通过 TRAF2 的 K63 连接泛素化加剧脂多糖诱导的小鼠急性肺损伤。
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S1P defects cause a new entity of cataract, alopecia, oral mucosal disorder, and psoriasis-like syndrome.S1P 缺陷导致一种新的白内障、脱发、口腔黏膜疾病和银屑病样综合征。
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ADAM17, A Key Player of Cardiac Inflammation and Fibrosis in Heart Failure Development During Chronic Catecholamine Stress.ADAM17，慢性儿茶酚胺应激期间心力衰竭发展中心脏炎症和纤维化的关键参与者。
Front Cell Dev Biol. 2021 Dec 13;9:732952. doi: 10.3389/fcell.2021.732952. eCollection 2021.
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