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.
Highlights
Cytokinesis is the final stage of cell division when two daughter cells are physically separated
Unc-51-like kinase 3 (ULK3) binds to endosomal sorting complexes required for transport (ESCRT)-III via tandem MIT domains
This approach revealed that ULK3 bound the ESCRT-III subunit IST1, an interaction not tested by Y2H because IST1 fusion constructs activated transcription non
Summary
Cytokinesis is the final stage of cell division when two daughter cells are physically separated. Midbody abscission occurs adjacent to the Flemming body, a central protein complex, and is mediated by the ESCRT pathway (endosomal sorting complexes required for transport) (Carlton and Martin-Serrano, 2007; Morita et al, 2007). Location-specific adaptors initially recruit the early-acting ALIX and ESCRT-I/-II factors, which recruit the lateacting ESCRT-III and VPS4 complexes to mediate membrane fission. In late stages of cytokinesis, the Flemming body protein CEP55 binds TSG101 (ESCRT-I) and ALIX, which leads to ESCRT-III subunit recruitment (Carlton and Martin-Serrano, 2007; Morita et al, 2007; Carlton et al, 2008). MIT domains bind short motifs within the C-terminal tails of ESCRT-III proteins called MIMs (MIT-interacting motifs), which become exposed and Caballe et al eLife 2015;4:e06547.
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