YAP and TAZ Mediators at the Crossroad between Metabolic and Cellular Reprogramming

Abstract

Cell reprogramming can either refer to a direct conversion of a specialized cell into another or to a reversal of a somatic cell into an induced pluripotent stem cell (iPSC). It implies a peculiar modification of the epigenetic asset and gene regulatory networks needed for a new cell, to better fit the new phenotype of the incoming cell type. Cellular reprogramming also implies a metabolic rearrangement, similar to that observed upon tumorigenesis, with a transition from oxidative phosphorylation to aerobic glycolysis. The induction of a reprogramming process requires a nexus of signaling pathways, mixing a range of local and systemic information, and accumulating evidence points to the crucial role exerted by the Hippo pathway components Yes-Associated Protein (YAP) and Transcriptional Co-activator with PDZ-binding Motif (TAZ). In this review, we will first provide a synopsis of the Hippo pathway and its function during reprogramming and tissue regeneration, then we introduce the latest knowledge on the interplay between YAP/TAZ and metabolism and, finally, we discuss the possible role of YAP/TAZ in the orchestration of the metabolic switch upon cellular reprogramming.

Keywords: TAZ; YAP; cell reprogramming; iPSC; metabolic reprogramming.

Figure 1

The Hippo signaling pathway comprises a cascade of phosphorylation and activation of kinases, which ultimately regulate YAP and TAZ subcellular localization. When the pathway is on, the activation of LATS1/2 triggers the inhibitory phosphorylation of YAP and TAZ. Phosphorylation on different residues may cause their cytoplasmic retention and/or their degradation through the ubiquitin-proteasome pathway. YAP can also be degraded by autophagy. When the pathway is off, YAP/TAZ dephosphorylation allows their nuclear import, where they compete with VGLL4 for binding to TEAD transcription factors to induce the expression of target genes.

Figure 2

The activity of YAP/TAZ is influenced by various metabolic cues. Some of them can activate YAP and TAZ, such as high levels of glucose, the monosaturated fatty acid biosynthetic pathway and the mevalonate pathway, IIGF signaling and mTOR. Some others, like low glucose condition and glucagon stimulation, act by inactivating YAP/TAZ. YAP and TAZ, in turn, influence cell metabolism in various ways (see the text for more details).

Figure 3

Cell reprogramming is accompanied by a decrease in OXPHOS and an increase in glycolysis. Shortly after reprogramming begins, cells undergo a transient hyperenergetic metabolism, which generates ROS, leading to the activation of HIF1, which further stimulates metabolic reprogramming together with c-MYC, NRF2, AKT and Lin28. A direct transcriptional regulation of glycolytic genes depends also on pluripotency factors OCT4, SOX2 and Nanog. YAP/TAZ activation may regulate the switch from OXPHOS to glycolysis in cell reprogramming, promoting glucose uptake and utilization, enhancing glutaminolysis, regulating the expression of metabolic genes, affecting epigenetic modifications to chromatin structure and post-transcriptional miRNA processing. Red arrows before ROS and HK2 mean “increased expression”.