Loss of ATP2C1 function promotes trafficking and degradation of NOTCH1: Implications for Hailey‐Hailey disease

Author:

Zonfrilli Azzurra1,Truglio Federica1,Simeone Alessandra1,Pelullo Maria2,De Turris Valeria2ORCID,Benelli Dario1,Checquolo Saula3,Bellavia Diana1,Palermo Rocco1,Uccelletti Daniela4,Screpanti Isabella1,Cialfi Samantha1ORCID,Talora Claudio1

Affiliation:

1. Department of Molecular Medicine Sapienza University of Rome Rome Italy

2. CLN2S‐Center for Life Nano‐ & Neuro‐Sciences Istituto Italiano di Tecnologia Rome Italy

3. Department of Medico‐Surgical Sciences and Biotechnology Sapienza University of Rome Latina Italy

4. Department of Biology and Biotechnology “C. Darwin” Sapienza University of Rome Rome Italy

Abstract

AbstractHailey‐Hailey disease (HHD) is a rare autosomal dominantly inherited disorder caused by mutations in the ATP2C1 gene that encodes an adenosine triphosphate (ATP)‐powered calcium channel pump. HHD is characterized by impaired epidermal cell‐to‐cell adhesion and defective keratinocyte growth/differentiation. The mechanism by which mutant ATP2C1 causes HHD is unknown and current treatments for affected individuals do not address the underlying defects and are ineffective. Notch signalling is a direct determinant of keratinocyte growth and differentiation. We found that loss of ATP2C1 leads to impaired Notch1 signalling, thus deregulation of the Notch signalling response is therefore likely to contribute to HHD manifestation. NOTCH1 is a transmembrane receptor and upon ligand binding, the intracellular domain (NICD) translocates to the nucleus activating its target genes. In the context of HHD, we found that loss of ATP2C1 function promotes upregulation of the active NOTCH1 protein (NICD‐Val1744). Here, deeply exploring this aspect, we observed that NOTCH1 activation is not associated with the transcriptional enhancement of its targets. Moreover, in agreement with these results, we found a cytoplasmic localization of NICD‐Val1744. We have also observed that ATP2C1‐loss is associated with the degradation of NICD‐Val1744 through the lysosomal/proteasome pathway. These results show that ATP2C1‐loss could promote a mechanism by which NOTCH1 is endocytosed and degraded by the cell membrane. The deregulation of this phenomenon, finely regulated in physiological conditions, could in HHD lead to the deregulation of NOTCH1 with alteration of skin homeostasis and disease manifestation.

Funder

Ministero dell’Istruzione, dell’Università e della Ricerca

Publisher

Wiley

Subject

Dermatology,Molecular Biology,Biochemistry

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3