INPP5E Preserves Genomic Stability through Regulation of Mitosis

Abstract

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. 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.

Induction of an Alternative mRNA 5′ Leader Enhances Translation of the Ciliopathy Gene Inpp5e and Resistance to Oncolytic Virus Infection

“…Thus, INPP5E antiviral activities may be not related to its ciliary localization. Away from the plasma membrane, centrosomal PIs can also be affected by a lack of INPP5E, leading to spindle microtubule destabilization, possibly through an imbalance in PI(4,5)P 2 expression (Sierra Potchanant et al, 2017). Whether these mechanisms have a role to play in mediating the enhanced virus binding and infection seen in 4T1 cells is subject to future investigation.…”

“…Our sentinel gene, INPP5E, is a target of genetic mutation in humans, responsible for ciliopathies such as Joubert syndrome and mental retardation, truncal obesity, retinal dystro-phy, and micropenis (MORM) syndrome (Jacoby et al, 2009). Mainly localized at the primary cilium, it has also been observed within the nucleus and at centrioles (Sierra Potchanant et al, 2017). Our IF data in poly(I:C)-or VACV-treated cells shows a punctate distribution pattern of induced INPP5E that is reminiscent of vesicles.…”

Induction of an alternative 5’ leader enhances translation of Inpp5e and resistance to oncolytic virus infection

“…INPP5E is a target of genetic mutation responsible for ciliopathies such as Joubert and MORM syndromes 58,59 . Mainly localized at the primary cilium, it has also been observed within the nucleus and at centrioles 60 . Our immunofluorescence data shows virusinduced INPP5E present throughout the cell but with globular foci at perinuclear structures and proximal to the plasma membrane.…”

“…also be affected by a lack of INPP5E, leading to spindle microtubule destabilization, possibly through an imbalance in PI(4,5)P2 expression 60 . Whether these mechanisms have a role to play in mediating the enhanced virus binding and infection that is seen in 4T1 cells is the subject of future investigation.…”

Dissecting the mechanisms of cell division

“…For example, folate deficiency leads to replicative stress during DNA replication and consequently to mis-segregation defects during mitosis (118). Similarly, the lipid family of phosphoinositides was shown to directly influence mitotic progression through proteins like NuMA (119) or phosphatases (120) and by regulating cytoskeletal elements (121,122). Sterols have also been shown to play a role in cell division: cells deprived of cholesterol have difficulty undergoing cytokinesis (123), and the cholesterol derivative pregnenolone localizes to the spindle poles, binds Shugoshin 1, and promotes centriole cohesion (124).…”