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Cytokinesis occurs during the last phase of cell division and distributes the cytoplasm of one parent cell into 2 daughter cells. This is driven by the formation of a so-called cleavage furrow resulting in the pinching inward of the plasma membrane to split the cell into 2 cells. The cleavage furrow ingression requires an actomyosin-based contractile ring composed of F-actin and myosin and the regulators to modulate the assembly and constriction of the contractile ring including scaffolding proteins and specific lipids.1 To ensure successful cytokinesis, the contractile ring and the regulatory factors need to be localized and assembled correctly at the cleavage furrow. In this volume of Cell Cycle, Sundvold et al., suggest that Arv1 is the protein that recruits myosin to the cleavage furrow by interacting with IQGAP1, a myosin-interacting IQ-motif-containing GTPase-activating protein.2
Arv1 was originally identified as a protein essential for viability of budding yeast that lacks 2 acyl-coenzyme A cholesterol acyltransferase-related enzymes, Are1 and Are2. Arv1 is an endoplasmic reticulum (ER) membrane protein with multiple transmembrane domains and is conserved from yeast to human. Deletion of yeast ARV1 gene leads to altered sterol distribution, abnormal sphingolipid and fatty acid metabolism, and to defects in PI(4,5)P2 polarization and glycosylphosphatidylinositol (GPI) synthesis. Loss of mammalian Arv1 function also results in defects in cholesterol homeostasis. Human Arv1 can fully complement the phenotypes of the yeast strain lacking Arv1,3 suggesting that functions of Arv1 are conserved throughout eukaryotic domain of life.
Sundvold et al. show that Arv1 becomes localized to the cell equator when the sister chromatids segregate into daughter cells during anaphase.2 In early telophase, Arv1 is further enriched at the cleavage furrow and remains enriched until late telophase. This cell cycle-dependent localization of Arv1 raises the question whether Arv1 regulates assembly of the contractile ring. Indeed, Arv1 interacts with EPLIN, which has been shown to regulate the formation of the actomyosin ring, and the cells deprived of EPLIN exhibit a reduced accumulation of Arv1 at the cleavage furrow (Fig. 1). These findings suggest that EPLIN recruits Arv1 to the cleavage furrow. Additionally, quantification of multinuclear cells and cells in telophase in Arv1-deprived cells reveal that Arv1 facilitates progression through telophase.
Next, Sundvold et al. show that Arv1 not only interacts with EPLIN for its recruitment to the cleavage furrow, but it also interacts with myosin and IQGAP1.2 Because Arv1 depletion reduces accumulation of myosin and IQGAP1 at the cleavage furrow, whereas depleting IQGAP1 does not affect accumulation of Arv1, the authors propose that Arv1 recruits myosin at the furrow by interacting with IQGAP1. Moreover, the authors show that Arv1 is dispensable for localization of F-actin and regulators of the contractile ring; RhoA, anillin, and that the Arv1-mediated recruitment of IQGAP1 or myosin is not dependent on cellular cholesterol levels, suggesting specific recruitment of myosin by a molecular pathway independent of RhoA, anillin and cholesterol (Fig. 1).
This study raises some questions that remain to be answered. Does Arv1-mediated recruitment of myosin depend on sphingolipid metabolism or GPI synthesis? Inhibition of sphingolipid or GPI synthesis perturbs cytokinesis raising the possibility that sphingolipid/GPI-anchored protein-enriched domains serve as platforms for proper assembly of the contractile ring. Another intriguing question is how membrane-associated Arv1 is delivered and accumulated to the cleavage furrow. This process may involve a direct interaction with EPLIN. Several studies in yeast and higher eukaryotic organisms have demonstrated that Arv1 proteins are localized to the ER. ER localization was not examined in full detail in the current study by Sundvold et al. The ER network seems to remain intact throughout mitosis.4 In telophase, ER luminal protein GRP-170, but not ER membrane protein Sec61, is enriched at the cleavage furrow,4,5 suggesting that ER domains may be differently arranged during mitosis. Intriguingly, GPI synthesis activities segregate into an ER domain that is associated with mitochondria.6 As mitochondria are recruited to the cleavage furrow during cytokinesis,5 ER contact sites with mitochondria may play a role in targeting of Arv1-associated ER domain to the furrow (Fig. 1). A recent study in fission yeast shows that ER contact sites function to modulate the distribution of ring components.7 Finally, whether the function of Arv1 in regulation of cytokinesis is evolutionarily conserved remains an open question.
No potential conflicts of interest were disclosed.