ULK3 regulates cytokinetic abscission by phosphorylating ESCRT-III proteins

Abstract

The endosomal sorting complexes required for transport (ESCRT) machinery mediates the physical separation between daughter cells during cytokinetic abscission. This process is regulated by the abscission checkpoint, a genome protection mechanism that relies on Aurora B and the ESCRT-III subunit CHMP4C to delay abscission in response to chromosome missegregation. In this study, we show that Unc-51-like kinase 3 (ULK3) phosphorylates and binds ESCRT-III subunits via tandem MIT domains, and thereby, delays abscission in response to lagging chromosomes, nuclear pore defects, and tension forces at the midbody. Our structural and biochemical studies reveal an unusually tight interaction between ULK3 and IST1, an ESCRT-III subunit required for abscission. We also demonstrate that IST1 phosphorylation by ULK3 is an essential signal required to sustain the abscission checkpoint and that ULK3 and CHMP4C are functionally linked components of the timer that controls abscission in multiple physiological situations.DOI: http://dx.doi.org/10.7554/eLife.06547.001

PRL-3 disrupts epithelial architecture by altering the post-mitotic midbody position

“…The molecular mechanisms underlying the timing of asymmetric abscission in epithelial cells are thought to be complex and include an abscission checkpoint that is still not well understood (Caballe et al, 2015; Lafaurie-Janvore et al, 2013). We did not observe a defect in the ploidy of the cells, which makes a disruption of the furrow regression rather unlikely.…”

“…We did not observe a defect in the ploidy of the cells, which makes a disruption of the furrow regression rather unlikely. One possible scenario is that PRL-3 could be acting downstream of Aurora kinase B, causing a failure in abscission delay – for example, by counteracting Unc-51-like kinase 3, which is needed for the final stages of abscission (Caballe et al, 2015). In general, the knowledge of the roles and involvement of particular phosphatases in cytokinesis is very limited (Caballe et al, 2015).…”

“…One possible scenario is that PRL-3 could be acting downstream of Aurora kinase B, causing a failure in abscission delay – for example, by counteracting Unc-51-like kinase 3, which is needed for the final stages of abscission (Caballe et al, 2015). In general, the knowledge of the roles and involvement of particular phosphatases in cytokinesis is very limited (Caballe et al, 2015). However, although PRL-3 localizes to the site of cytokinesis, it is unclear if its involvement is direct or indirect given that PRL-3 expression in cells affects a plethora of pathways (Rios et al, 2013).…”

Autophagy and the Cell Cycle: A Complex Landscape

“…In addition, an autophagy-independent function for unc-51-like autophagy-activating kinase 3 (ULK3) as an abscission regulator has been reported (134). Abscission is mediated by the endosomal sorting complexes required for transport (ESCRT) machinery, which mediates membrane remodeling in a number of processes including cytokinesis, viral budding, and autophagy (135).…”

“…The timing of abscission is regulated by the abscission checkpoint, which delays abscission in response to a number of mitotic abnormalities (136). Interestingly, ULK3 was shown to function in the abscission checkpoint to delay abscission by phosphorylating and binding ESCRT-III subunits in response to lagging chromosomes, nuclear pore defects, and tension forces at the midbody (134). Thus, ULK3 appears to function as an integral part of the abscission checkpoint machinery.…”