State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
Cell Rep. 2023 Jul 25;42(7):112690. doi: 10.1016/j.celrep.2023.112690. Epub 2023 Jun 27.
AKT kinase is a key regulator in cell metabolism and survival, and its activation is strictly modulated. Herein, we identify XAF1 (XIAP-associated factor) as a direct interacting protein of AKT1, which strongly binds the N-terminal region of AKT1 to block its K63-linked poly-ubiquitination and subsequent activation. Consistently, Xaf1 knockout causes AKT activation in mouse muscle and fat tissues and reduces body weight gain and insulin resistance induced by high-fat diet. Pathologically, XAF1 expression is low and anti-correlated with the phosphorylated p-T308-AKT signal in prostate cancer samples, and Xaf1 knockout stimulates the p-T308-AKT signal to accelerate spontaneous prostate tumorigenesis in mice with Pten heterozygous loss. And ectopic expression of wild-type XAF1, but not the cancer-derived P277L mutant, inhibits orthotopic tumorigenesis. We further identify Forkhead box O 1 (FOXO1) as a transcriptional regulator of XAF1, thus forming a negative feedback loop between AKT1 and XAF1. These results reveal an important intrinsic regulatory mechanism of AKT signaling.
AKT 激酶是细胞代谢和存活的关键调节因子，其激活受到严格调控。本文中，我们鉴定出 XAF1（XIAP 相关因子）是 AKT1 的直接相互作用蛋白，它强烈结合 AKT1 的 N 端区域，阻止其 K63 连接的多聚泛素化及其随后的激活。一致地，Xaf1 敲除导致小鼠肌肉和脂肪组织中 AKT 的激活，并减少高脂肪饮食诱导的体重增加和胰岛素抵抗。在病理上，XAF1 的表达水平较低，与前列腺癌样本中磷酸化的 p-T308-AKT 信号呈负相关，Xaf1 敲除会刺激 p-T308-AKT 信号，加速具有 Pten 杂合缺失的小鼠自发发生前列腺肿瘤。而过表达野生型 XAF1（而非源自癌症的 P277L 突变体）则抑制原位肿瘤的发生。我们进一步鉴定出叉头框蛋白 O1（FOXO1）是 XAF1 的转录调节因子，从而在 AKT1 和 XAF1 之间形成负反馈回路。这些结果揭示了 AKT 信号的一个重要内在调节机制。
