Details

Autor(en) / Beteiligte

• 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
• Tan, Xu

Titel

Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility

Ist Teil von

• Nature genetics, 2016-12, Vol.48 (12), p.1508-1516

Ort / Verlag

United States

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.