Identification of XAF1 as an endogenous AKT inhibitor

• Published in: Cell reports (Cambridge) 2023-07, Vol.42 (7), p.112690-112690, Article 112690
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; AKT; Animals; Apoptosis - physiology; Apoptosis Regulatory Proteins - metabolism; Carcinogenesis; FOXO1; Intracellular Signaling Peptides and Proteins - metabolism; Male; metabolism; Mice; Neoplasm Proteins - metabolism; Neoplasms; phosphorylation; prostate cancer; Proto-Oncogene Proteins c-akt - metabolism; ubiquitination; XAF1
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112690

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. [Display omitted] •XAF1 specifically interacts with the PH domain and disordered linker region of AKT1•XAF1 suppresses the K63-linked ubiquitination of AKT1 to inhibit its activation•XAF1 modulates metabolic phenotypes and tumorigenesis via AKT1•FOXO1 transcriptionally regulates XAF1 to inhibit AKT activation Chen et al. identify XAF1 as an endogenous AKT inhibitor interfering with AKT1 cell membrane localization and T308 phosphorylation by blocking AKT1 K63-linked ubiquitination through direct interaction. They further identify that XAF1 is transcriptionally regulated by FOXO1 forming a double-negative feedback loop in AKT regulation via the FOXO1-XAF1 axis.