Bibliographic Details
| Title: |
The human AAA-ATPase VPS4A isoform and its co-factor VTA1 have a unique function in regulating mammalian cytokinesis abscission. |
| Authors: |
Dvilansky, Inbar1,2 (AUTHOR), Altaras, Yarin1,2 (AUTHOR), Kamenetsky, Nikita1,2 (AUTHOR), Nachmias, Dikla1,2 (AUTHOR), Elia, Natalie1,2 (AUTHOR) elianat@post.bgu.ac.il |
| Superior Title: |
PLoS Biology. 4/30/2024, Vol. 22 Issue 4, p1-21. 21p. |
| Subject Terms: |
*CYTOKINESIS, *CELL division, *HUMAN abnormalities, *CELL lines, *HUMAN beings |
| Abstract: |
Mutations in the human AAA-ATPase VPS4 isoform, VPS4A, cause severe neurodevelopmental defects and congenital dyserythropoietic anemia (CDA). VPS4 is a crucial component of the endosomal sorting complex required for transport (ESCRT) system, which drives membrane remodeling in numerous cellular processes, including receptor degradation, cell division, and neural pruning. Notably, while most organisms encode for a single VPS4 gene, human cells have 2 VPS4 paralogs, namely VPS4A and VPS4B, but the functional differences between these paralogs is mostly unknown. Here, we set out to investigate the role of the human VPS4 paralogs in cytokinetic abscission using a series of knockout cell lines. We found that VPS4A and VPS4B hold both overlapping and distinct roles in abscission. VPS4A depletion resulted in a more severe abscission delay than VPS4B and was found to be involved in earlier stages of abscission. Moreover, VPS4A and a monomeric-locked VPS4A mutant bound the abscission checkpoint proteins CHMP4C and ANCHR, while VPS4B did not, indicating a regulatory role for the VPS4A isoform in abscission. Depletion of VTA1, a co-factor of VPS4, disrupted VPS4A-ANCHR interactions and accelerated abscission, suggesting that VTA1 is also involved in the abscission regulation. Our findings reveal a dual role for VPS4A in abscission, one that is canonical and can be compensated by VPS4B, and another that is regulatory and may be delivered by its monomeric form. These observations provide a potential mechanistic explanation for the neurodevelopmental defects and other related disorders reported in VPS4A-mutated patients with a fully functional VPS4B paralog. The human AAA-ATPase VPS4 facilitates the complete separation between daughter cells at the end of cytokinesis. It has two paralogs, VPS4A and VPS4B, but whether there are functional differences between them is unknown. This study shows that VPS4A has unique regulatory functions in cytokinesis for which VPS4B cannot compensate, explaining the neurodevelopmental defects recently reported in people with mutations in VPS4A. [ABSTRACT FROM AUTHOR] |
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