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

Abstract

Cytokinesis is the final stage of cell division. Successful cytokinesis requires membrane trafficking pathways regulated by Rabs, molecular switches activated by guanine nucleotide exchange factors (GEFs). Late in cytokinesis, an intercellular cytokinetic bridge (ICB) connecting the two daughter cells undergoes abscission, which requires depolymerization of actin. Rab35 recruits MICAL1 to oxidate and depolymerize actin filaments. We report that DENND2B, a protein previously implicated in cancer, mental retardation and multiple congenital disorders functions as a GEF for Rab35 and recruits and activates the GTPase at the ICB. Unexpectedly, the N terminal region of DENND2B interacts with an active mutant of Rab35, suggesting that DENND2B is both a Rab35 GEF and effector. Knockdown of DENND2B delays abscission resulting in increased multinucleated cells and over-accumulation of F-actin at the ICB. F-actin accumulation leads to formation of a chromatin bridge, a process known to activate the NoCut/abscission checkpoint, and DENND2B knockdown actives Aurora B kinase, a hallmark of checkpoint activation. This study identifies DENND2B as a crucial player in cytokinetic abscission and provides insight into the multisystem disorder associated with DENND2B mutation.

A neurodevelopmental disorder associated with a loss-of-function missense mutation in RAB35

“…For instance, patients with a pathogenic missense variant in a gene involved in regulating cytokinesis exhibited intellectual disability and microcephaly ( 53 ). Recently, we identified that Rab35 is recruited to the cytokinetic bridge via its interaction with DENND2B, which functions as a GEF and effector for the GTPase ( 54 ), and promotes F-actin oxidation by Rab35 effector MICAL1 ( 30 ). It is likely that Rab35 R27H is not recruited to the cytokinetic bridge or is unable to promote successful cytokinetic abscission because of lack of interaction with effectors.…”