title: Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.
abstract: Skin integrity is essential for protection from external stress and trauma. Defects in structural proteins such as keratins cause skin fragility, epitomized by epidermolysis bullosa (EB), a life-threatening disorder. Here we show that dominant mutations of KLHL24, encoding a cullin 3-RBX1 ubiquitin ligase substrate receptor, cause EB. We have identified start-codon mutations in the KLHL24 gene in five patients with EB. These mutations lead to truncated KLHL24 protein lacking the initial 28 amino acids (KLHL24-ΔN28). KLHL24-ΔN28 is more stable than its wild-type counterpart owing to abolished autoubiquitination. We have further identified keratin 14 (KRT14) as a KLHL24 substrate and found that KLHL24-ΔN28 induces excessive ubiquitination and degradation of KRT14. Using a knock-in mouse model, we have confirmed that the Klhl24 mutations lead to stabilized Klhl24-ΔN28 and cause Krt14 degradation. Our findings identify a new disease-causing mechanism due to dysregulation of autoubiquitination and open new avenues for the treatment of related disorders.
authors: Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China.
authors: Zhimiao
authors: Z
authors: Lin
authors: School of Pharmaceutical Sciences, Center for Infectious Disease Research, School of Medicine, Tsinghua University, Tsinghua-Peking Center for Life Sciences, Beijing, China.
authors: Shuo
authors: S
authors: Li
authors: Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China.
authors: Cheng
authors: C
authors: Feng
authors: School of Pharmaceutical Sciences, Center for Infectious Disease Research, School of Medicine, Tsinghua University, Tsinghua-Peking Center for Life Sciences, Beijing, China.
authors: Shang
authors: S
authors: Yang
authors: Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China.|Peking-Tsinghua Center for Life Sciences, Beijing, China.
authors: Huijun
authors: H
authors: Wang
authors: School of Pharmaceutical Sciences, Center for Infectious Disease Research, School of Medicine, Tsinghua University, Tsinghua-Peking Center for Life Sciences, Beijing, China.
authors: Danhui
authors: D
authors: Ma
authors: Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China.|Peking-Tsinghua Center for Life Sciences, Beijing, China.
authors: Jing
authors: J
authors: Zhang
authors: School of Pharmaceutical Sciences, Center for Infectious Disease Research, School of Medicine, Tsinghua University, Tsinghua-Peking Center for Life Sciences, Beijing, China.
authors: Mengting
authors: M
authors: Gou
authors: Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China.
authors: Dingfang
authors: D
authors: Bu
authors: School of Pharmaceutical Sciences, Center for Infectious Disease Research, School of Medicine, Tsinghua University, Tsinghua-Peking Center for Life Sciences, Beijing, China.
authors: Tengjiang
authors: T
authors: Zhang
authors: School of Pharmaceutical Sciences, Center for Infectious Disease Research, School of Medicine, Tsinghua University, Tsinghua-Peking Center for Life Sciences, Beijing, China.
authors: Xiaohui
authors: X
authors: Kong
authors: Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China.
authors: Xintong
authors: X
authors: Wang
authors: Department of Dermatology, Tel Aviv Sourasky Medical Centre, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Ofer
authors: O
authors: Sarig
authors: Laboratory of Electron Microscopy, Peking University First Hospital, Beijing, China.
authors: Yali
authors: Y
authors: Ren
authors: BGI-Shenzhen, Shenzhen, China.
authors: Lanlan
authors: L
authors: Dai
authors: BGI-Shenzhen, Shenzhen, China.
authors: Hankui
authors: H
authors: Liu
authors: BGI-Shenzhen, Shenzhen, China.
authors: Jianguo
authors: J
authors: Zhang
authors: National Institute of Biological Sciences, Beijing, China.
authors: Fei
authors: F
authors: Li
authors: Laboratory Animal Facility, Peking University First Hospital, Beijing, China.
authors: Yongyan
authors: Y
authors: Hu
authors: Department of Dermatology, Tel Aviv Sourasky Medical Centre, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Gilly
authors: G
authors: Padalon-Brauch
authors: Department of Dermatology, Tel Aviv Sourasky Medical Centre, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Dan
authors: D
authors: Vodo
authors: Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.
authors: Feng
authors: F
authors: Zhou
authors: National Institute of Biological Sciences, Beijing, China.
authors: Ting
authors: T
authors: Chen
authors: MOE Key Laboratory of Bioinformatics, School of Life Sciences and Centre of Biomedical Analysis, Tsinghua University, Beijing, China.
authors: Haiteng
authors: H
authors: Deng
authors: Department of Dermatology, Tel Aviv Sourasky Medical Centre, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Eli
authors: E
authors: Sprecher
authors: Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China.|Peking-Tsinghua Center for Life Sciences, Beijing, China.
authors: Yong
authors: Y
authors: Yang
authors: School of Pharmaceutical Sciences, Center for Infectious Disease Research, School of Medicine, Tsinghua University, Tsinghua-Peking Center for Life Sciences, Beijing, China.
authors: Xu
authors: X
authors: Tan
mesh_terms: D000328:Adult; D000818:Animals; D016022:Case-Control Studies; D002675:Child, Preschool; D004820:Epidermolysis Bullosa / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D053547:Keratin-14 / Q000378:metabolism*; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D059748:Proteolysis; D012097:Repressor Proteins / Q000235:genetics*; D012867:Skin / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C584157:KLHL24 protein, human; D053547:Keratin-14; D012097:Repressor Proteins; D025801:Ubiquitin