title: Pathogenic Cx31 is un/misfolded to cause skin abnormality via a Fos/JunB-mediated mechanism.
abstract: Mutations in connexin-31 (Cx31) are associated with multiple human diseases, including familial erythrokeratodermia variabilis (EKV). The pathogenic mechanism of EKV-associated Cx31 mutants remains largely elusive. Here, we show that EKV-pathogenic Cx31 mutants are un/misfolded and temperature sensitive. In Drosophila, expression of pathogenic Cx31, but not wild-type Cx31, causes depigmentation and degeneration of ommatidia that are rescued by expression of either dBip or dHsp70. Ectopic expression of Cx31 in mouse skin results in skin abnormalities resembling human EKV. The affected tissues show remarkable disrupted gap junction formation and significant upregulation of chaperones Bip and Hsp70 as well as AP-1 proteins c-Fos and JunB, in addition to molecular signatures of skin diseases. Consistently, c-Fos, JunB, Bip and Hsp70 are strikingly higher in keratinocytes of EKV patients than their matched control individuals. Furthermore, a druggable AP-1 inhibitory small molecule suppresses skin phenotype and pathological abnormalities of transgenic Cx31 mice. The study suggests that Cx31 mutant proteins are un/misfolded to cause EKV likely via an AP-1-mediated mechanism and identifies a small molecule with therapeutic potential of the disease.
authors.affiliation: Institute of Precision Medicine, the Third Xiangya Hospital, and the State Key Laboratory of Medical Genetics.
authors.forename: Chengyuan
authors.initials: C
authors.lastname: Tang
authors.affiliation: Institute of Precision Medicine, the Third Xiangya Hospital, and the State Key Laboratory of Medical Genetics, Department of Dermatology, Xiangya Hospital, Xiangya Medical School, Central South University, Changsha, Hunan 410078, China and.
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.affiliation: Institute of Precision Medicine, the Third Xiangya Hospital, and the State Key Laboratory of Medical Genetics.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Chi
authors.affiliation: Institute of Precision Medicine, the Third Xiangya Hospital, and the State Key Laboratory of Medical Genetics.
authors.forename: Dawei
authors.initials: D
authors.lastname: Yang
authors.affiliation: Institute of Precision Medicine, the Third Xiangya Hospital, and the State Key Laboratory of Medical Genetics.
authors.forename: Shu
authors.initials: S
authors.lastname: Liu
authors.affiliation: Institute of Precision Medicine, the Third Xiangya Hospital, and the State Key Laboratory of Medical Genetics.
authors.forename: Mujun
authors.initials: M
authors.lastname: Liu
authors.affiliation: Institute of Precision Medicine, the Third Xiangya Hospital, and the State Key Laboratory of Medical Genetics.
authors.forename: Qian
authors.initials: Q
authors.lastname: Pan
authors.affiliation: Illumina, Inc., San Diego, CA 92121, USA.
authors.forename: Jianbing
authors.initials: J
authors.lastname: Fan
authors.affiliation: Institute of Precision Medicine, the Third Xiangya Hospital, and the State Key Laboratory of Medical Genetics.
authors.forename: Danling
authors.initials: D
authors.lastname: Wang
authors.affiliation: Institute of Precision Medicine, the Third Xiangya Hospital, and the State Key Laboratory of Medical Genetics, zhangzhuohua@sklmg.edu.cn.
authors.forename: Zhuohua
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001577:Benzophenones / Q000494:pharmacology; D054910:Compound Eye, Arthropod / Q000473:pathology; D017630:Connexins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics; D056266:Erythrokeratodermia Variabilis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D051379:Mice; D009154:Mutation; D010858:Pigmentation / Q000235:genetics; D017510:Protein Folding; D058767:Protein Unfolding; D057165:Proteostasis Deficiencies / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011993:Recombinant Fusion Proteins; D012867:Skin / Q000473:pathology; D013312:Stress, Physiological; D013696:Temperature; D035362:Transcription Factor TFIID / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C568912:3-(5-(4-(cyclopentyloxy)-2-hydroxybenzoyl)-2-((3-hydroxy-1,2-benzisoxazol-6-yl)methoxy)phenyl)propionic acid; C432688:BIP2 protein, Drosophila; D001577:Benzophenones; D017630:Connexins; D029721:Drosophila Proteins; D018840:HSP70 Heat-Shock Proteins; D007555:Isoxazoles; C581727:JunB protein, human; D016760:Proto-Oncogene Proteins c-fos; D011993:Recombinant Fusion Proteins; D035362:Transcription Factor TFIID; D014157:Transcription Factors; C068044:GJB3 protein, human