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

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: Zhimiao Lin, Shuo Li, Cheng Feng, Shang Yang, Huijun Wang, Danhui Ma, Jing Zhang, Mengting Gou, Dingfang Bu, Tengjiang Zhang, Xiaohui Kong, Xintong Wang, Ofer Sarig, Yali Ren, Lanlan Dai, Hankui Liu, Jianguo Zhang, Fei Li, Yongyan Hu, Gilly Padalon-Brauch, Dan Vodo, Feng Zhou, Ting Chen, Haiteng Deng, Eli Sprecher, Yong Yang & Xu Tan

Influence Factor: 27.958

Citation: Nat Genet 48, 1508-1516 (2016).

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