Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Nat Commun. 2013;4:2633. doi: 10.1038/ncomms3633.
Cytokine-induced activation of signal transducer and activator of transcription 3 (STAT3) promotes the regrowth of damaged axons in the adult central nervous system (CNS). Here we show that KLF4 physically interacts with STAT3 upon cytokine-induced phosphorylation of tyrosine 705 (Y705) on STAT3. This interaction suppresses STAT3-dependent gene expression by blocking its DNA-binding activity. The deletion of KLF4 in vivo induces axon regeneration of adult retinal ganglion cells (RGCs) via Janus kinase (JAK)-STAT3 signalling. This regeneration can be greatly enhanced by exogenous cytokine treatment, or removal of an endogenous JAK-STAT3 pathway inhibitor called suppressor of cytokine signalling 3 (SOCS3). These findings reveal an unexpected cross-talk between KLF4 and activated STAT3 in the regulation of axon regeneration that might have therapeutic implications in promoting repair of injured adult CNS.
细胞因子诱导信号转导子和转录激活子 3（STAT3）的激活促进了成年中枢神经系统（CNS）中受损轴突的再生。在这里，我们发现 KLF4 在 STAT3 的酪氨酸 705（Y705）被细胞因子诱导磷酸化时与 STAT3 发生物理相互作用。这种相互作用通过阻断其 DNA 结合活性来抑制 STAT3 依赖性基因表达。体内 KLF4 的缺失通过 Janus 激酶（JAK）-STAT3 信号通路诱导成年视网膜神经节细胞（RGC）的轴突再生。通过外源性细胞因子处理或去除称为细胞因子信号转导抑制因子 3（SOCS3）的内源性 JAK-STAT3 通路抑制剂，可以大大增强这种再生。这些发现揭示了 KLF4 和激活的 STAT3 之间在调节轴突再生中的意外串扰，这可能对促进损伤成年中枢神经系统的修复具有治疗意义。
