Identification of XAF1 as an endogenous AKT inhibitor

作者：Chen, Min; Wang, Kangjunjie; Han, Ying; Yan, Shukun; Yuan, Huairui; Liu, Qiuli; Li, Long; Li, Ni; Zhu, Hongwen; Lu, Dayun; Wang, Kaihua; Liu, Fen; Luo, Dakui; Zhang, Yuxue; Jiang, Jun; Li, Dali; Zhang, Lei; Ji, Hongbin; Zhou, Hu; Chen, Yong^*; Qin, Jun^*; Gao, Daming^*

来源：Cell Reports, 2023, 42(7): 112690.

DOI：10.1016/j.celrep.2023.112690

• X-LINKED INHIBITOR
• PROTEIN-KINASE B
• HEPATIC GLUCONEOGENESIS
• PI3K/AKT PATHWAY
• PROSTATE-CANCER
• PHOSPHORYLATION
• ACTIVATION
• EXPRESSION
• SKP2
• GENE

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.

• 单位
  中国科学院; 中国科学院研究生院; y; 复旦大学