Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Genes Dev. 2023 Mar 1;37(5-6):191-203. doi: 10.1101/gad.350320.122.
Subcellular localization of messenger RNA (mRNA) is a widespread phenomenon that can impact the regulation and function of the encoded protein. In nonneuronal cells, specific mRNAs localize to cell protrusions, and proper mRNA localization is required for cell migration. However, the mechanisms by which mRNA localization regulates protein function in this setting remain unclear. Here, we examined the functional consequences of localization of the mRNA encoding KIF1C. KIF1C is a kinesin motor protein required for cell migration and mRNA trafficking, including trafficking of its own mRNA. We show that mRNA localization does not regulate KIF1C's protein abundance, distribution, or ability to traffic other mRNAs. Conversely, mRNA localization to protrusions is required for directed cell migration. We used mass spectrometry to identify binding partners of endogenous KIF1C, which revealed dramatic dysregulation of the number and identity of KIF1C interactors in response to mRNA mislocalization. These results therefore uncovered a mechanistic connection between mRNA localization to cell protrusions and the specificity of protein-protein interactions. We anticipate that this mechanism is not limited to and is likely to be a general principle that impacts the functions of proteins encoded by protrusion-enriched mRNAs in nonneuronal cells.
信使 RNA（mRNA）的亚细胞定位是一种广泛存在的现象，它可以影响编码蛋白的调控和功能。在非神经元细胞中，特定的 mRNA 定位于细胞突起处，mRNA 的正确定位是细胞迁移所必需的。然而，在这种情况下，mRNA 定位调节蛋白功能的机制尚不清楚。在这里，我们研究了编码 KIF1C 的 mRNA 定位的功能后果。KIF1C 是一种驱动蛋白马达蛋白，对于细胞迁移和 mRNA 运输，包括其自身 mRNA 的运输是必需的。我们表明，mRNA 定位并不调节 KIF1C 的蛋白丰度、分布或运输其他 mRNA 的能力。相反，mRNA 向突起的定位是定向细胞迁移所必需的。我们使用质谱法鉴定了内源性 KIF1C 的结合伙伴，这揭示了响应 mRNA 定位错误，KIF1C 相互作用体的数量和身份出现了显著失调。因此，这些结果揭示了 mRNA 向细胞突起定位与蛋白-蛋白相互作用特异性之间的机制联系。我们预计，这种机制不仅限于 KIF1C，而且很可能是一个普遍的原则，影响非神经元细胞中突起富集 mRNA 编码的蛋白质的功能。
