title: 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.
authors.affiliation: Department of Infectious Diseases, King's College London School of Medicine, London, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Caballe
authors.affiliation: Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, United States.
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Wenzel
authors.affiliation: Department of Infectious Diseases, King's College London School of Medicine, London, United Kingdom.
authors.forename: Monica
authors.initials: M
authors.lastname: Agromayor
authors.affiliation: Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, United States.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Alam
authors.affiliation: Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, United States.
authors.forename: Jack J
authors.initials: JJ
authors.lastname: Skalicky
authors.affiliation: Department of Infectious Diseases, King's College London School of Medicine, London, United Kingdom.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kloc
authors.affiliation: Department of Infectious Diseases, King's College London School of Medicine, London, United Kingdom.
authors.forename: Jeremy G
authors.initials: JG
authors.lastname: Carlton
authors.affiliation: Department of Infectious Diseases, King's College London School of Medicine, London, United Kingdom.
authors.forename: Leticia
authors.initials: L
authors.lastname: Labrador
authors.affiliation: Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, United States.
authors.forename: Wesley I
authors.initials: WI
authors.lastname: Sundquist
authors.affiliation: Department of Infectious Diseases, King's College London School of Medicine, London, United Kingdom.
authors.forename: Juan
authors.initials: J
authors.lastname: Martin-Serrano
mesh_terms: D002460:Cell Line; D048749:Cytokinesis; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D006801:Humans; D015513:Oncogene Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C541008:CHMP4C protein, human; D056827:Endosomal Sorting Complexes Required for Transport; C533705:IST1 protein, human; D015513:Oncogene Proteins; D017346:Protein Serine-Threonine Kinases; C547386:ULK3 protein, human
keywords: ESCRT; ULK3; abscission checkpoint; biochemistry; cell biology; cytokinesis; human; phosphorylation