TAZ is a WW domain containing a transcription coactivator that modulates mesenchymal differentiation and development of multiple organs. In this study, we show that TAZ is phosphorylated by the Lats tumor suppressor kinase, a key component of the Hippo pathway, whose alterations result in organ and tissue hypertrophy in Drosophila and contribute to tumorigenesis in humans. Lats phosphorylates TAZ on several serine residues in the conserved HXRXXS motif and creates 14-3-3 binding sites, leading to cytoplasmic retention and functional inactivation of TAZ. Ectopic expression of TAZ stimulates cell proliferation, reduces cell contact inhibition, and promotes epithelial-mesenchymal transition (EMT). Elimination of the Lats phosphorylation sites results in a constitutively active TAZ, enhancing the activity of TAZ in promoting cell proliferation and EMT. Our results elucidate a molecular mechanism for TAZ regulation and indicate a potential function of TAZ as an important target of the Hippo pathway in regulating cell proliferation tumorigenesis.

The anti-hyperglycemic effect of metformin is believed to be caused by its direct action on signaling processes in hepatocytes, leading to lower hepatic gluconeogenesis. Recently, metformin was reported to alter the gut microbiota community in humans, suggesting that the hyperglycemia-lowering action of the drug could be the result of modulating the population of gut microbiota. However, the critical microbial signaling metabolites and the host targets associated with the metabolic benefits of metformin remained elusive. Here, we performed metagenomic and metabolomic analysis of samples from individuals with newly diagnosed type 2 diabetes (T2D) naively treated with metformin for 3 d, which revealed that Bacteroides fragilis was decreased and the bile acid glycoursodeoxycholic acid (GUDCA) was increased in the gut. These changes were accompanied by inhibition of intestinal farnesoid X receptor (FXR) signaling. We further found that high-fat-diet (HFD)-fed mice colonized with B. fragilis were predisposed to more severe glucose intolerance, and the metabolic benefits of metformin treatment on glucose intolerance were abrogated. GUDCA was further identified as an intestinal FXR antagonist that improved various metabolic endpoints in mice with established obesity. Thus, we conclude that metformin acts in part through a B. fragilis–GUDCA–intestinal FXR axis to improve metabolic dysfunction, including hyperglycemia.

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The TAZ transcription co-activator promotes cell proliferation and epithelial-mesenchymal transition. TAZ is inhibited by the Hippo tumor suppressor pathway, which promotes TAZ cytoplasmic localization by phosphorylation. We report here that TAZ protein stability is controlled by a phosphodegron recognized by the F-box protein ␤-TrCP and ubiquitylated by the SCF/CRL1 ␤-TrCP E3 ligase. The interaction between TAZ and ␤-TrCP is regulated by the Hippo pathway. Phosphorylation of a phosphodegron in TAZ by LATS primes it for further phosphorylation by CK1⑀ and subsequent binding by ␤-TrCP. Therefore, the Hippo pathway negatively regulates TAZ function by both limiting its nuclear accumulation and promoting its degradation. The phosphodegron-mediated TAZ degradation plays an important role in negatively regulating TAZ biological functions.