Targeting Canonical and Non-Canonical STAT Signaling Pathways in Renal Diseases

Abstract

Signal transducer and activator of transcription (STAT) plays an essential role in the inflammatory reaction and immune response of numerous renal diseases. STATs can transmit the signals of cytokines, chemokines, and growth factors from the cell membrane to the nucleus. In the canonical STAT signaling pathways, upon binding with their cognate receptors, cytokines lead to a caspase of Janus kinases (JAKs) and STATs tyrosine phosphorylation and activation. Besides receptor-associated tyrosine kinases JAKs, receptors with intrinsic tyrosine kinase activities, G-protein coupled receptors, and non-receptor tyrosine kinases can also activate STATs through tyrosine phosphorylation or, alternatively, other post-translational modifications. Activated STATs translocate into the nucleus and mediate the transcription of specific genes, thus mediating the progression of various renal diseases. Non-canonical STAT pathways consist of preassembled receptor complexes, preformed STAT dimers, unphosphorylated STATs (U-STATs), and non-canonical functions including mitochondria modulation, microtubule regulation and heterochromatin stabilization. Most studies targeting STAT signaling pathways have focused on canonical pathways, but research extending into non-canonical STAT pathways would provide novel strategies for treating renal diseases. In this review, we will introduce both canonical and non-canonical STAT pathways and their roles in a variety of renal diseases.

Keywords: STAT; renal diseases; signal transduction.

Figure 1

Canonical STAT signaling pathways (solid lines) and STAT endogenous inhibitors (dashed lines). Cytokines binding to cognate receptors causes the cytokine receptors dimerization. The caspase of Janus kinases (JAKs) and STATs are phosphorylated and activated. Phosphorylated STATs dissociate from the receptors, form homodimers or heterodimers, and transfer to the nucleus. Intranuclear STATs bind to specific DNA elements and activate the transcription of cytokine-responsive genes. Protein tyrosine phosphatases (PTPs) dephosphorylate activated pSTATs in the nucleus and dissociate STATs. Then, STATs are exported into the cytoplasm. Suppressors of cytokine signaling (SOCS) are upregulated in response to ligands stimulation and inhibit JAK/STAT pathways through different mechanisms: SOCS1 binds to and inhibits JAKs; SOCS3 binds to JAK-proximal sites on cytokine receptors and inhibits JAK activities; CIS competes and blocks STATs binding to the docking site of cytokine receptors. Constitutive protein inhibitors of activated STATs (PIAS) interact with pSTAT dimers in the nucleus upon cytokine stimulation and inhibit STAT transcription activity through different mechanisms: PIAS1/3 binds to STATs and blocks DNA binding; PIASy/x recruit other co-repressor molecules such as histone deacetylases (HDACs) to inhibit STATs-mediated gene transcription; PIAS1 may promote the SUMOylation of STATs.

Figure 2

Non-canonical STAT signaling pathways. Non-canonical dynamics aspects (blue lines) include preassembled cytokine receptor complexes in the absence of ligands, preformed STAT dimers in the absence of the activating tyrosine, and non-phosphorylated latent nuclear STAT molecules consistently located in the nucleus. The question marks indicate that the mechanisms are unclear and still need to be further explored. Non-canonical functions include regulation of mitochondria (green lines), microtubule (yellow lines), and heterochromatin (red lines). Tyrosine phosphorylation of STATs promotes their serine phosphorylation. P-Ser-STAT3 is imported into mitochondria via GRIM-19. MitoStat3 promotes ATP synthesis, decreases ROS release, and increases mitochondrial Ca²⁺ and MPTP opening through regulating electron transport chains I, II, and V. Stathmin inhibits microtubule growth by binding tubulin dimers and sequestering tubulin, which decreases the concentration of free heterodimers available to polymerization. Phosphorylated STAT3 binding to stathmin inhibits its tubulin depolymerization activity. Unphosphorylated latent STAT binds to HP1 on heterochromatin in the nucleus. Phosphorylated STATs reduce the amount of unphosphorylated STAT localized on heterochromatin. HP1 disassociates from heterochromatin and leads to heterochromatin instability. Genes originally localized in heterochromatin are now accessible to STATs or other transcription factors.

Figure 3

Overview of STAT signaling pathways involved in renal diseases. Ligands-receptors-kinases-STAT axis can mediate different biological events and regulate numerous renal diseases. Yellow circles: typical receptor tyrosine kinases JAKs. Green boxes: non-receptor tyrosine kinases SFK. Red fonts: non-canonical functions of STAT signaling pathways.