División de Neurobiología Molecular y Celular, Instituto de Biología Celular y Neurociencias (IBCN)-CONICET-UBA, Facultad de Medicina, University of Buenos Aires (UBA), CP1121, Buenos Aires, Argentina.
Laboratorio de Transporte Axonal y Enfermedades Neurodegenerativas, Instituto de Biología Celular y Neurociencias (IBCN)-CONICET-UBA, Facultad de Medicina, University of Buenos Aires (UBA), CP1121, Buenos Aires, Argentina.
Cell Mol Life Sci. 2020 Jun;77(11):2217-2233. doi: 10.1007/s00018-019-03282-3. Epub 2019 Aug 22.
The molecular mechanisms that control the biosynthetic trafficking, surface delivery, and degradation of TrkA receptor are essential for proper nerve growth factor (NGF) function, and remain poorly understood. Here, we identify Tetraspanin1 (Tspan1) as a critical regulator of TrkA signaling and neuronal differentiation induced by NGF. Tspan1 is expressed by developing TrkA-positive dorsal root ganglion (DRG) neurons and its downregulation in sensory neurons inhibits NGF-mediated axonal growth. In addition, our data demonstrate that Tspan1 forms a molecular complex with the immature form of TrkA localized in the endoplasmic reticulum (ER). Finally, knockdown of Tspan1 reduces the surface levels of TrkA by promoting its preferential sorting towards the autophagy/lysosomal degradation pathway. Together, these data establish a novel homeostatic role of Tspan1, coordinating the biosynthetic trafficking and degradation of TrkA, regardless the presence of NGF.
控制 TrkA 受体生物合成运输、表面递呈和降解的分子机制对于神经营养因子（NGF）的正常功能至关重要，但目前仍知之甚少。在这里，我们发现 Tetraspanin1（Tspan1）是 TrkA 信号和 NGF 诱导的神经元分化的关键调节因子。Tspan1 由发育中的 TrkA 阳性背根神经节（DRG）神经元表达，其在感觉神经元中的下调抑制了 NGF 介导的轴突生长。此外，我们的数据表明，Tspan1 与定位于内质网（ER）中的不成熟形式的 TrkA 形成一个分子复合物。最后，Tspan1 的敲低通过促进其优先分选到自噬/溶酶体降解途径来降低 TrkA 的表面水平。总之，这些数据确立了 Tspan1 的新的稳态作用，协调了 TrkA 的生物合成运输和降解，无论是否存在 NGF。
