Cytokinesis proceeds through spatiotemporally tightly controlled events orchestrated by cellular machineries regulating microtubule and actin dynamics, membrane trafficking and fusion, ultimately leading to cleavage furrow ingression, intercellular bridge formation and physical separation of the two daughter cells by abscission. Molecular mechanisms controlling cytokinetic abscission are emerging, but its spatiotemporal and molecular control still remains incompletely understood, especially in vivo .
Accurate control of cytokinesis and abscission is crucial for correct partitioning of the genetic material between the two daughter cells. Failure of cytokinesis may give rise to tetraploid cells with multiple centrosomes, which may result in chromosomal missegregation, genetic instability and aneuploidy that might contribute to cancer progression. How defects in cytokinesis and abscission might contribute to cancer development in different tissues in vivo still requires further investigation.
To address these questions in a multicellular context in vivo we use Drosophila melanogaster as a model organism. In parallel, we study cytokinesis in human cultured cells to identify evolutionarily conserved mechanisms.
Endosomal sorting required for transport (ESCRT) -III is an evolutionarily conserved protein complex that forms spiral-like filaments to mediate membrane scission in cellular processes, including endosome maturation, virus budding and cytokinetic abscission (Vietri M, Raduovic M and Stenmark H, Nat Rev Mol Cell , 2020). During cytokinetic abscission in human cells, centrosomal protein of 55 kDa (CEP55) recruits the scaffold protein ALIX and ESCRT-I / -II to the midbody, which in turn coordinately promotes midbody recruitment of ESCRT-III that mediates abscission ( Figure 1 ).
Our work has uncovered that ALIX interacts with the ESCRT-III subunit Shrub to promote cytokinetic abscission in Drosophila female germline stem cells (Eikenes et al. , PLoS Genetics , 2015) ( Figure 1 ), showing a role for ALIX / ESCRT-III in cytokinetic abscission in a multicellular context. We have further elucidated that the centralspindlin subunit Pavarotti directly interacts with Drosophila ALIX to recruit it to the midbody via a mechanism resembling virus budding (Lie-Jensen et al. , Current Biology , 2019) ( Figure 1). Our results highlight an evolutionarily conserved role for the centralspindlin complex in recruiting key abscission factors to the midbody ( Figure 1 ).
To understand the control of cytokinetic abscission in further detail, we now continue deciphering the spatiotemporal dynamics and molecular control of ALIX and associated proteins in vivo and in human cells. We further address any tumor suppressive roles of these proteins in vivo .