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Cited by 13Microtubule and mitosis dynamicsCellular transport and secretionProtein Kinase Regulation and GTPase Signaling

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DENND2B activates Rab35 at the intercellular bridge, regulating cytokinetic abscission and tetraploidy

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Kumar, Rahul, Francis, Vincent, Ioannou, Maria S., Aguila, Adriana, Khan, Maleeha, Banks, Emily, Kulasekaran, Gopinath, McPherson, Peter S.·2023·Cell Reports
DOI 10.1016/j.celrep.2023.112795

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Abstract

Cytokinesis relies on membrane trafficking pathways regulated by Rabs and guanine nucleotide exchange factors (GEFs). During cytokinesis, the intercellular cytokinetic bridge (ICB) connecting daughter cells undergoes abscission, which requires actin depolymerization. Rab35 recruits MICAL1 to oxidize and depolymerize actin filaments. We show that DENND2B, a protein linked to cancer and congenital disorders, functions as a Rab35 GEF, recruiting and activating Rab35 at the ICB. DENND2B's N-terminal region also interacts with an active form of Rab35, suggesting that DENND2B is both a Rab35 GEF and effector. Knockdown of DENND2B delays abscission, leading to multinucleated cells and filamentous actin (F-actin) accumulation at the ICB, impairing recruitment of ESCRT-III at the abscission site. Additionally, F-actin accumulation triggers the formation of a chromatin bridge, activating the NoCut/abscission checkpoint, and DENND2B knockdown activates Aurora B kinase, a hallmark of checkpoint activation. Thus, our study identifies DENND2B as a crucial player in cytokinetic abscission.

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Metadata

Authors
Kumar, R., Francis, V., Ioannou, M. S., Aguila, A., Khan, M., Banks, E., Kulasekaran, G., & McPherson, P. S.
Affiliations
Montreal Neurological Institute and Hospital (CA)
Corresponding author
  • Kumar, Rahul
  • McPherson, Peter S.
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2023-07
Volume
42
Issue
7
Pages
112795
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2023.112795
OpenAlex
W4384432201
Cited by
13
References
1
Citations by year
2026: 5 · 2025: 4 · 2024: 3 · 2023: 1
FWCI
1.88
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Canadian Institutes of Health Research
  • Fonds de Recherche du Québec - Santé
  • McGill University
  • Royal Society of Canada (Rab35)
  • ALS Society of Canada
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
Rab35, guanine nucleotide exchange factor, cytokinetic abscission, actin depolymerization, MICAL1, ESCRT-III, chromatin bridges, Aurora B kinase, tetraploidy, multinucleated cells, Rab
MeSH terms
Calponins, Actins, DNA-Binding Proteins, HeLa Cells, Humans, Mixed Function Oxygenases, Microfilament Proteins, Actin Cytoskeleton, Guanine Nucleotide Exchange Factors, rab GTP-Binding Proteins, Tumor Suppressor Proteins, Cytokinesis, Endosomal Sorting Complexes Required for Transport, Tetraploidy

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