Abstract
ABSTRACTThe partially understood phosphoinositide signaling cascade regulates multiple aspects of cellular metabolism. Previous studies revealed that INPP5E, the inositol polyphosphate-5-phosphatase that is mutated in the developmental disorders Joubert and MORM syndromes, is essential for the function of the primary cilium and maintenance of phosphoinositide balance in nondividing cells. Here, we report that INPP5E further contributes to cellular homeostasis by regulating cell division. We found that silencing or genetic knockout of INPP5E in human and murine cells impairs the spindle assembly checkpoint, centrosome and spindle function, and maintenance of chromosomal integrity. Consistent with a cell cycle regulatory role, we found that INPP5E expression is cell cycle dependent, peaking at mitotic entry. INPP5E localizes to centrosomes, chromosomes, and kinetochores in early mitosis and shuttles to the midzone spindle at mitotic exit. Our findings identify the previously unknown, essential role of INPP5E in mitosis and prevention of aneuploidy, providing a new perspective on the function of this phosphoinositide phosphatase in health and development.
Highlights
The partially understood phosphoinositide signaling cascade regulates multiple aspects of cellular metabolism
To confirm that INPP5E phosphatase activity is depleted upon INPP5E knockdown, we confirmed that HeLa cells stably expressing INPP5E short hairpin RNA (shRNA) contain more total PI[4,5]P2 than control cells as determined by using a quantitative enzyme-linked immunosorbent assay (ELISA) (Fig. 3C)
We found that INPP5E functions outside interphase as a regulator of paclitaxeltriggered spindle assembly checkpoint (SAC) (Fig. 2) and multiple stages of mitosis (Fig. 5)
Summary
The partially understood phosphoinositide signaling cascade regulates multiple aspects of cellular metabolism. Previous studies revealed that INPP5E, the inositol polyphosphate-5-phosphatase that is mutated in the developmental disorders Joubert and MORM syndromes, is essential for the function of the primary cilium and maintenance of phosphoinositide balance in nondividing cells. Previous studies have demonstrated that INPP5E regulates ciliary function in nondividing cells, but the role of this phosphatase during cell division had not been examined in detail. We show that INPP5E expression is cell cycle dependent and that INPP5E shuttles to the mitotic apparatus in dividing cells to impact centrosome and spindle function. These novel roles of INPP5E in cell division may be related to the roles of this phosphatase in development and cancer
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