Calderilla-Barbosa Luis, Seibenhener M Lamar, Du Yifeng, Diaz-Meco Maria-Theresa, Moscat Jorge, Yan Jin, Wooten Marie W, Wooten Michael C
Department of Biological Sciences, 331 Funchess Hall, Auburn University, Auburn, AL 36849, USA.
10901 North Torrey Pines Road, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
J Cell Sci. 2014 Sep 15;127(Pt 18):4052-63. doi: 10.1242/jcs.152363. Epub 2014 Jul 11.
The dynein motor protein complex is required for retrograde transport of vesicular cargo and for transport of aggregated proteins along microtubules for processing and degradation at perinuclear aggresomes. Disruption of this process leads to dysfunctional endosome accumulation and increased protein aggregation in the cell cytoplasm, both pathological features of neurodegenerative diseases. However, the exact mechanism of dynein functionality in these pathways is still being elucidated. Here, we show that the scaffolding protein SQSTM1 directly interacts with dynein through a previously unidentified dynein-binding site. This interaction is independent of HDAC6, a known interacting protein of both SQSTM1 and dynein. However, knockdown of HDAC6 increases the interaction of SQSTM1 with dynein, indicating a possible competitive interaction. Using different dynein cargoes, we show that SQSTM1 is required for proper dynein motility and trafficking along microtubules. Based on our results, we propose a new model of competitive interaction between SQSTM1 and HDAC6 with dynein. In this model, SQSTM1 would not only affect the association of polyubiquitylated protein aggregates and endosomes with dynein, but would also be required for normal dynein function.
动力蛋白复合物对于囊泡货物的逆行运输以及聚集蛋白沿着微管的运输是必需的，这些聚集蛋白会在核周聚集体中进行加工和降解。该过程的破坏会导致功能失调的内体积累以及细胞质中蛋白质聚集增加，而这两者都是神经退行性疾病的病理特征。然而，动力蛋白在这些途径中的具体功能机制仍在被阐明。在此，我们表明支架蛋白SQSTM1通过一个先前未被识别的动力蛋白结合位点直接与动力蛋白相互作用。这种相互作用独立于HDAC6，HDAC6是SQSTM1和动力蛋白二者已知的相互作用蛋白。然而，敲低HDAC6会增加SQSTM1与动力蛋白的相互作用，这表明可能存在竞争性相互作用。使用不同的动力蛋白货物，我们表明SQSTM1对于动力蛋白沿着微管的正常运动和运输是必需的。基于我们的结果，我们提出了一个关于SQSTM1和HDAC6与动力蛋白之间竞争性相互作用的新模型。在这个模型中，SQSTM1不仅会影响多聚泛素化蛋白聚集体和内体与动力蛋白的结合，而且对于动力蛋白的正常功能也是必需的。
