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Significance Orientation of the mitotic spindle relative to the cell cortex is known to control the orientation of the cell division plane, thereby contributing to cell fate specification and tissue organization. The molecular mechanisms of how spindle orientation is regulated during mitosis remain poorly defined. In this paper, we demonstrate that cylindromatosis (CYLD) regulates spindle orientation via its dual functions as a microtubule-associated protein and deubiquitinase. CYLD stabilizes astral microtubules, hence ensuring microtubule extension to the cell cortex and interaction with cortical sites. The deubiquitinase activity of CYLD, however, catalyzes the removal of the polyubiquitin chain from dishevelled and thereby promotes the dishevelled-NuMA-dynein/dynactin complex formation at the cell cortex, a requirement for generating pulling forces on astral microtubules.

CYLD regulates spindle orientation by stabilizing astral microtubules and promoting dishevelled-NuMA-dynein/dynactin complex formation