Wareham Lauren K, Echevarria Franklin D, Sousa Jennifer L, Konlian Danielle O, Dallas Gabrielle, Formichella Cathryn R, Sankaran Priya, Goralski Peter J, Gustafson Jenna R, Sappington Rebecca M
Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Neuroscience Graduate Program, Vanderbilt University, Nashville, TN 37232, USA.
iScience. 2021 Sep 16;24(10):103141. doi: 10.1016/j.isci.2021.103141. eCollection 2021 Oct 22.
The interleukin-6 (IL-6) family of cytokines and its downstream effector, STAT3, are important mediators of neuronal health, repair, and disease throughout the CNS, including the visual system. Here, we elucidate a transcription-independent mechanism for the neuropoietic activities of IL-6 related to axon development, regeneration, and repair. We examined the outcome of IL-6 deficiency on structure and function of retinal ganglion cell (RGC) axons, which form the optic projection. We found that IL-6 deficiency substantially delays anterograde axon transport . The reduced rate of axon transport is accompanied by changes in morphology, structure, and post-translational modification of microtubules. and studies in mice and swine revealed that IL-6-dependent microtubule phenotypes arise from protein-protein interactions between STAT3 and stathmin. As in tumor cells and T cells, this STAT3-stathmin interaction stabilizes microtubules in RGCs. Thus, this IL-6-STAT3-dependent mechanism for axon architecture is likely a fundamental mechanism for microtubule stability systemically.
细胞因子白细胞介素-6（IL-6）家族及其下游效应因子信号转导和转录激活因子3（STAT3）是整个中枢神经系统（包括视觉系统）中神经元健康、修复和疾病的重要介质。在此，我们阐明了IL-6与轴突发育、再生和修复相关的神经生成活动的一种不依赖转录的机制。我们研究了IL-6缺乏对形成视神经投射的视网膜神经节细胞（RGC）轴突结构和功能的影响。我们发现，IL-6缺乏会显著延迟轴突的顺向运输。轴突运输速率降低伴随着微管形态、结构和翻译后修饰的变化。对小鼠和猪的研究表明，IL-6依赖的微管表型源于STAT3与微管解聚蛋白之间的蛋白质-蛋白质相互作用。与肿瘤细胞和T细胞一样，这种STAT3-微管解聚蛋白相互作用使RGC中的微管稳定。因此，这种依赖IL-6-STAT3的轴突结构机制可能是全身微管稳定性的一种基本机制。
