PtdIns(3)P controls cytokinesis through KIF13A-mediated recruitment of FYVE-CENT to the midbody.
Several subunits of the class III phosphatidylinositol-3-OH kinase (PI(3)K-III) complex are known as tumour suppressors. Here we uncover a function for this complex and its catalytic product phosphatidylinositol-3-phosphate (PtdIns(3)P) in cytokinesis. We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. Translocation of FYVE-CENT and TTC19 from the centrosome to the midbody requires another FYVE-CENT-interacting protein, the microtubule motor KIF13A. Depletion of the VPS34 or Beclin 1 subunits of PI(3)K-III causes cytokinesis arrest and an increased number of binucleate and multinucleate cells, in a similar manner to the depletion of FYVE-CENT, KIF13A or TTC19. These results provide a mechanism for the translocation and docking of a cytokinesis regulatory machinery at the midbody.
Sagona
Antonia P
AP
Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, N-0310 Oslo, Norway.
Nezis
Ioannis P
IP
Pedersen
Nina Marie
NM
Liestøl
Knut
K
Poulton
John
J
Rusten
Tor Erik
TE
Skotheim
Rolf I
RI
Raiborg
Camilla
C
Stenmark
Harald
H
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000071186:Beclin-1; D015374:Biosensing Techniques; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D018385:Centrosome / Q000201:enzymology*; D048749:Cytokinesis; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D008938:Mitosis; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D008941:Spindle Apparatus / Q000201:enzymology*; D014162:Transfection
D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D002352:Carrier Proteins; D029721:Drosophila Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D016547:Kinesins; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D011993:Recombinant Fusion Proteins; C491997:BECN1 protein, human; C478397:CHMP4B protein, human; C417670:KIF13A protein, human; C528699:ZFYVE26 protein, human; C055525:phosphatidylinositol 3-phosphate