Abstract
Precise cell division is essential for multicellular development, and defects in this process have been linked to cancer. Septins are a family of proteins that are required for mammalian cell division, but their function and mode of regulation during this process are poorly understood. Here, we demonstrate that cyclin-dependent kinase 1 (Cdk1) phosphorylates septin 9 (SEPT9) upon mitotic entry, and this phosphorylation controls association with the proline isomerase, Pin1. Both SEPT9 and Pin1 are critical for mediating the final separation of daughter cells. Expression of mutant SEPT9 that is defective in Pin1 binding was unable to rescue cytokinesis defects caused by SEPT9 depletion but rather induced dominant-negative defects in cytokinesis. However, unlike SEPT9 depletion, Pin1 was not required for the accumulation of the exocyst complex at the midbody. These results suggest that SEPT9 plays multiple roles in abscission, one of which is regulated by the action of Cdk1 and Pin1.
Highlights
Evidence is lacking to explain how septin function is controlled during the cell cycle
cyclin-dependent kinase 1 (Cdk1) Phosphorylates Thr-24 in the N-terminal Region of septin 9 (SEPT9) in a Mitosis-specific Manner—We first addressed the possibility that SEPT9 may be regulated by phosphorylation during mitosis
Given that mammalian septins undergo dramatic changes in localization and possibly function at the onset of cell division, it has long been speculated that they may be regulated by the cell cycle machinery that controls mitotic entry [16]
Summary
Evidence is lacking to explain how septin function is controlled during the cell cycle. Recent studies have revealed that in cell lines, human septins, similar to those of yeast, form octameric complexes with SEPT9 at the terminal position [6, 7]. The function of the N terminus is not known, but we recently showed that only the longest three SEPT9 N-terminal variants (SEPT9_i1-SEPT9_i3) could rescue cytokinesis phenotypes caused by SEPT9 depletion, whereas shorter forms (SEPT9_i4) resulted in a dominant-negative abscission defect [13], indicating that the N termini of different isoforms control unique functions. Regulation of SEPT9 by Cdk and Pin forms of SEPT9, but lacking from the short forms, as a putative mitotic phosphorylation site [14, 15] This raises the possibility that phosphorylation of the N-terminal region of SEPT9_i1SEPT9_i3 may be important for their role during cell division. We show that Pin, similar to SEPT9, is required for abscission in human cells, and its depletion causes phenotypes similar to knockdown of SEPT9, controlling a previously uncharacterized step in abscission
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