An Update on the Multifaceted Roles of STAT3 in the Heart

Figure 1. The intracellular localization pattern of STAT3 affects autophagy regulation. The activation of STAT3 downstream of cytokine or tyrosine kinase receptors induces its Y705 phosphorylation and dimerization. STAT3 dimers translocate to the nucleus, where they bind to DNA in order to up- or down-regulate autophagy related genes. In addition to nuclear STAT3, unphosphorylated cytoplasmic STAT3 also regulates autophagy. Unphosphorylated cytoplasmic STAT3 sequesters FOXO and Eif2ak2. FOXO translocates into the nucleus and upregulates multiple autophagy-related genes, while Eif2ak2 phosphorylates Eif2A that regulates autophagy through its nuclear translocation. The image of DNA was adapted from Servier Medical Art (https://smart.servier.com/).

Figure 2. The involvement of STAT3 in the regulation of ER activity. STAT3 decreases cellular death under different conditions through its ER-dependent activity. Following I/R, JAK2-STAT3 pathway rescues SERCA expression and activity, which reduces the ER stress occurring during I/R injury. This reduces cell death and helps in inducing the infarct size. In addition, STAT3 modulates the ER-mitochondrial calcium release by directly interacting with IP3R3 and facilitating its degradation. This consequently leads to a decrease in the calcium release from ER to mitochondria, and thus causes a decrease in apoptotic cell death. The S727 STAT3 residue plays a regulatory role. The images of ER and mitochondria were adapted from Servier Medical Art (https://smart.servier.com/).

Figure 3. The involvement of STAT3 in cellular metabolism. STAT3 plays an important role in establishing glycolysis-dependent energy derivation, via the Warburg effect. This is mediated by several connections between STAT3 and hypoxia responsive factor 1 alpha (HIF-1α). Following oxygen deprivation (hypoxia), the levels of HIF-1α increase and cause an increase in pyruvate kinase 2 (PKM2) levels. PKM2 induces the phosphorylation of STAT3, which induces the expression of HIF-1α. In parallel, STAT3 also decreases the expression of mitochondrial genes. All these incidences finally favor anaerobic glycolysis and decrease electron transport chain activity and aerobic respiration. The images of DNA and mitochondria were adapted from Servier Medical Art (https://smart.servier.com/).