TAOK2 is an ER kinase that catalyzes the dynamic tethering of ER to microtubules

Abstract

The endoplasmic reticulum (ER) extensively associates with the microtubule cytoskeleton. Although integral to its many functions, mechanisms through which the ER tethers to microtubules and regulates its coupling dynamics with the cytoskeleton are poorly understood. Herein we report that TAOK2 is an ER-resident multifunctional protein kinase required for tethering of ER membranes to microtubules. Using biochemical and super-resolution imaging techniques, we show that TAOK2 is a multipass membrane-spanning kinase localized in distinct ER domains via four transmembrane and amphipathic helices. Using in vitro and cellular assays, we find that TAOK2 directly binds microtubules with high affinity. We define the minimal TAOK2 determinants that induce ER-microtubule tethering. While TAOK2 knockout cells exhibit decreased ER stability and disrupted movement of ER along growing microtubule plus-ends, motor-mediated ER motility is not affected. ER-microtubule tethering is tightly regulated by the catalytic activity of TAOK2 in interphase and mitotic cells. Perturbation of TAOK2 activity leads to defects in ER morphology and cell division. Our study identifies TAOK2 as an ER-microtubule tether, and reveals a kinase-regulated mechanism for control of ER dynamics critical for cell growth and division.