Zhang Zhao, Turer Emre, Li Xiaohong, Zhan Xiaoming, Choi Mihwa, Tang Miao, Press Amanda, Smith Steven R, Divoux Adeline, Moresco Eva Marie Y, Beutler Bruce
Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
Translational Research institute for Metabolism and Diabetes, Florida Hospital, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32827; Center for Metabolic Origins of Disease, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32827.
Proc Natl Acad Sci U S A. 2016 Oct 18;113(42):E6418-E6426. doi: 10.1073/pnas.1614467113. Epub 2016 Oct 5.
We describe a metabolic disorder characterized by lipodystrophy, hepatic steatosis, insulin resistance, severe diabetes, and growth retardation observed in mice carrying N-ethyl-N-nitrosourea (ENU)-induced mutations. The disorder was ascribed to a mutation of kelch repeat and BTB (POZ) domain containing 2 (Kbtbd2) and was mimicked by a CRISPR/Cas9-targeted null allele of the same gene. Kbtbd2 encodes a BTB-Kelch family substrate recognition subunit of the Cullin-3-based E3 ubiquitin ligase. KBTBD2 targeted p85α, the regulatory subunit of the phosphoinositol-3-kinase (PI3K) heterodimer, causing p85α ubiquitination and proteasome-mediated degradation. In the absence of KBTBD2, p85α accumulated to 30-fold greater levels than in wild-type adipocytes, and excessive p110-free p85α blocked the binding of p85α-p110 heterodimers to IRS1, interrupting the insulin signal. Both transplantation of wild-type adipose tissue and homozygous germ line inactivation of the p85α-encoding gene Pik3r1 rescued diabetes and hepatic steatosis phenotypes of Kbtbd2 mice. Kbtbd2 was down-regulated in diet-induced obese insulin-resistant mice in a leptin-dependent manner. KBTBD2 is an essential regulator of the insulin-signaling pathway, modulating insulin sensitivity by limiting p85α abundance.
我们描述了一种代谢紊乱疾病，其特征为脂肪营养不良、肝脂肪变性、胰岛素抵抗、严重糖尿病和生长发育迟缓，在携带N-乙基-N-亚硝基脲（ENU）诱导突变的小鼠中观察到。该疾病归因于含kelch重复序列和BTB（POZ）结构域的2（Kbtbd2）基因突变，并且可被同一基因的CRISPR/Cas9靶向无效等位基因模拟。Kbtbd2编码基于Cullin-3的E3泛素连接酶的BTB-Kelch家族底物识别亚基。KBTBD2靶向磷酸肌醇-3激酶（PI3K）异二聚体的调节亚基p85α，导致p85α泛素化和蛋白酶体介导的降解。在缺乏KBTBD2的情况下，p85α的积累水平比野生型脂肪细胞高30倍，过量的无p110的p85α阻断了p85α-p110异二聚体与IRS1的结合，中断了胰岛素信号。野生型脂肪组织移植和编码p85α的基因Pik3r1的纯合种系失活均挽救了Kbtbd2小鼠的糖尿病和肝脂肪变性表型。在饮食诱导的肥胖胰岛素抵抗小鼠中，Kbtbd2以瘦素依赖的方式下调。KBTBD2是胰岛素信号通路的关键调节因子，通过限制p85α丰度来调节胰岛素敏感性。
