PtdIns(4,5)P2 Functions at the Cleavage Furrow during Cytokinesis

Abstract

Phosphoinositides play important roles in regulating the cytoskeleton and vesicle trafficking, potentially important processes at the cleavage furrow. However, it remains unclear which, if any, of the phosphoinositides play a role during cytokinesis. A systematic analysis to determine if any of the phosphoinositides might be present or of functional importance at the cleavage furrow has not been published. Several studies hint at a possible role for one or more phosphoinositides at the cleavage furrow. The best of these are genetic data identifying mutations in phosphoinositide-modifying enzymes (a PtdIns(4)P-5-kinase in S. pombe and a PI-4-kinase in D. melanogaster) that interfere with cytokinesis. The genetic nature of these experiments leaves questions as to how direct may be their contribution to cytokinesis. Here we show that a single phosphoinositide, PtdIns(4,5)P2, specifically accumulates at the furrow. Interference with PtdIns(4,5)P2 interferes with adhesion of the plasma membrane to the contractile ring at the furrow. Finally, four distinct interventions to specifically interfere with PtdIns(4,5)P2 each impair cytokinesis. We conclude that PtdIns(4,5)P2 is present at the cleavage furrow and is required for normal cytokinesis at least in part because of a role in adhesion between the contractile ring and the plasma membrane.

Cytokinesis in Animal Cells

“…Consistent with this, the PI4-kinase Four-wheel drive (Fwd) and the PI(4)P binding protein GOLPH3 are both required for cytokinesis in Drosophila spermatocytes (Brill et al 2000;Polevoy et al 2009;Sechi et al 2014). Some evidence also indicates that the phosphoinositide phosphatidylinositol 4,5-biphosphate (PI(4,5)P2) is enriched at the cleavage furrows of dividing tissue culture cells and Drosophila spermatocytes, in which it regulates formation and stability of the cytokinetic ring (Field et al 2005b;Wong et al 2005;Echard 2012). PI(4,5)P2 interacts with the contractile ring components anillin and septins and regulates F-actin polymerization by modulating the activity of the actin-binding proteins profilin and cofilin (Yin and Janmey 2003;Bertin et al 2010;Liu et al 2012).…”

Actin regulation during abscission: unexpected roles of Rab35 and endocytic transport

“…Phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P 2 ) is a well-established regulator of the actin cytoskeleton during interphase. Recent work also has shown that PtdIns(4,5)P 2 accumulates at the cleavage furrow in yeast, Dictyostelium and mammalian cells [2,3]. Furthermore, inhibition of PtdIns(4,5) P 2 production leads to the failure of cytokinesis [2][3][4].…”

“…Recent work also has shown that PtdIns(4,5)P 2 accumulates at the cleavage furrow in yeast, Dictyostelium and mammalian cells [2,3]. Furthermore, inhibition of PtdIns(4,5) P 2 production leads to the failure of cytokinesis [2][3][4]. While the roles of PtdIns(4,5)P 2 during cytokinesis remains to be fully elucidated, at least some of its functions are known: the stabilization of the acto-myosin contractile ring, as well as the linking of the actin cytoskeleton to the plasma membrane by the virtue of its binding to septins and ERM (exrin/ radixin/moesin) proteins [5].…”

“…Since PtdIns(4,5)P 2 accumulation in the furrow is reminiscent of the polarization of PtdIns(4,5)P 2 during cell motility, it has been proposed that proteins such as phophatidylinositol-4-phosphate 5-kinase (PI5Kβ) and phosphatase and tensin homologue on chromosome 10 (PTEN) may also regulate PtdIns(4,5)P 2 accumulation at the ingressing furrow. Indeed, PI5Kβ and PTEN were shown to be enriched during furrow formation and be required for early cytokinesis [3,4]. What is much less understood is how the levels of PtdIns(4,5)P 2 are downregulated during abscission.…”

Palmitate impairs cytokinesis associated with RhoA inhibition

“…In addition, we found that two palmitoylation inhibitors, 2-bromopalmitate and cerulenin, and the mono-unsaturated fatty acid, oleate, could protect palmitate-treated cells from impaired cytokinesis with recovery of the suppressed RhoA activity (Supplementary information, Figure S4), implying that protein palmitoylation might be involved in the palmitate-induced cytokinetic failure. The role of lipids in cytokinesis has been recognized in some recent literatures [8][9][10]. Palmitate, as a free fatty acid, may potentially interfere with the function of these critical lipids, thereby inhibiting cytokinesis.…”