| Title | Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility |
| Authors | Lin, Zhimiao Li, Shuo Feng, Cheng Yang, Shang Wang, Huijun Ma, Danhui Zhang, Jing Gou, Mengting Bu, Dingfang Zhang, Tengjiang Kong, Xiaohui Wang, Xintong Sarig, Ofer Ren, Yali Dai, Lanlan Liu, Hankui Zhang, Jianguo Li, Fei Hu, Yongyan Padalon-Brauch, Gilly Vodo, Dan Zhou, Feng Chen, Ting Deng, Haiteng Sprecher, Eli Yang, Yong Tang, Xu |
| Affiliation | Peking Univ, Dept Dermatol, Hosp 1, Beijing Key Lab Mol Diag Dermatoses, Beijing, Peoples R China. Tsinghua Univ, Sch Pharmaceut Sci, Sch Med, Tsinghua Peking Ctr Life Sci,Ctr Infect Dis Res, Beijing, Peoples R China. Peking Tsinghua Ctr Life Sci, Beijing, Peoples R China. Tel Aviv Univ, Dept Dermatol, Tel Aviv Sourasky Med Ctr, Dept Human Mol Genet & Biochem,Sackler Fac Med, Tel Aviv, Israel. Peking Univ, Hosp 1, Electron Microscopy Lab, Beijing, Peoples R China. BGI Shenzhen, Shenzhen, Peoples R China. Natl Inst Biol Sci, Beijing, Peoples R China. Peking Univ, Hosp 1, Lab Anim Facil, Beijing, Peoples R China. Fudan Univ, Inst Biomed Sci, Shanghai Med Coll, Shanghai, Peoples R China. Tsinghua Univ, Sch Life Sci, MOE Key Lab Bioinformat, Beijing, Peoples R China. Tsinghua Univ, Ctr Biomed Anal, Beijing, Peoples R China. Peking Univ, Dept Dermatol, Hosp 1, Beijing Key Lab Mol Diag Dermatoses, Beijing, Peoples R China. Tang, X (reprint author), Tsinghua Univ, Sch Pharmaceut Sci, Sch Med, Tsinghua Peking Ctr Life Sci,Ctr Infect Dis Res, Beijing, Peoples R China. Yang, Y (reprint author), Peking Tsinghua Ctr Life Sci, Beijing, Peoples R China. |
| Keywords | EPIDERMOLYSIS-BULLOSA SIMPLEX PROTEASOME PATHWAY MUSCULAR-DYSTROPHY BTB/KELCH PROTEIN KAINATE RECEPTORS GENE FAMILY DEGRADATION EPITHELIA DISEASE DOMAIN |
| Issue Date | 2016 |
| Publisher | NATURE GENETICS |
| Citation | NATURE GENETICS.2016,48(12),1508-1516. |
| 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-Delta N28). KLHL24-Delta N28 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-Delta N28 induces excessive ubiquitination and degradation of KRT14. Using a knock-in mouse model, we have confirmed that the K1h124 mutations lead to stabilized K1h124-Delta N28 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. |
| URI | http://hdl.handle.net/20.500.11897/457181 |
| ISSN | 1061-4036 |
| DOI | 10.1038/ng.3701 |
| Indexed | SCI(E) PubMed |
| Appears in Collections: | 第一医院 |
