Department of Anatomy and Cell Biology, University of Illinois at Chicago, IL, USA.
Department of Anatomy and Cell Biology, University of Illinois at Chicago, IL, USA
ASN Neuro. 2015 Jan 30;7(1). doi: 10.1177/1759091414568186. Print 2015 Jan-Feb.
The HIV glycoprotein gp120, a neurotoxic HIV glycoprotein that is overproduced and shed by HIV-infected macrophages, is associated with neurological complications of HIV such as distal sensory polyneuropathy, but interactions of gp120 in the peripheral nervous system remain to be characterized. Here, we demonstrate internalization of extracellular gp120 in a manner partially independent of binding to its coreceptor CXCR4 by F11 neuroblastoma cells and cultured dorsal root ganglion neurons. Immunocytochemical and pharmacological experiments indicate that gp120 does not undergo trafficking through the endolysosomal pathway. Instead, gp120 is mainly internalized through lipid rafts in a cholesterol-dependent manner, with a minor fraction being internalized by fluid phase pinocytosis. Experiments using compartmentalized microfluidic chambers further indicate that, after internalization, endocytosed gp120 selectively undergoes retrograde but not anterograde axonal transport from axons to neuronal cell bodies. Collectively, these studies illuminate mechanisms of gp120 internalization and axonal transport in peripheral nervous system neurons, providing a novel framework for mechanisms for gp120 neurotoxicity.
HIV 糖蛋白 gp120 是一种过度产生和由感染 HIV 的巨噬细胞释放的神经毒性 HIV 糖蛋白，与 HIV 的神经并发症有关，如远端感觉多发性神经病，但 gp120 在周围神经系统中的相互作用仍有待阐明。在这里，我们证明了 F11 神经母细胞瘤细胞和培养的背根神经节神经元以部分独立于与其核心受体 CXCR4 结合的方式内化细胞外 gp120。免疫细胞化学和药理学实验表明，gp120 不会通过内体溶酶体途径进行运输。相反，gp120 主要通过胆固醇依赖性的质膜小窝内化，一小部分通过液相胞吞作用内化。使用分隔式微流控室的实验进一步表明，内化后，内吞的 gp120 选择性地从轴突逆行但不是顺行地向神经元细胞体进行轴突运输。总的来说，这些研究阐明了外周神经系统神经元中 gp120 内化和轴突运输的机制，为 gp120 神经毒性的机制提供了新的框架。
