Cytokinesis in development and carcinogenesis

The overall aim of the research in my project group is to elucidate molecular mechanisms of cytokinesis, the final step of cell division, and to elucidate whether defects in the machineries controlling cytokinesis might be involved in carcinogenesis.

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 .

Figure 1. Mechanisms of cytokinetic abscission in Drosophila and human cells. Left panel: Our work has elucidated that ALIX and ESCRT-III/Shrub interact to promote cytokinetic abscission in Drosophila melanogaster (Eikenes et al., PLoS Genetics, 2015) and that the centralspindlin complex recruits ALIX to the midbody via interactions with the ALIX-V-domain via a mechanism similar to virus budding (Lie-Jensen et al., Current Biology, 2019). This bypasses the need of CEP55 that is required in human cells (see right panel). Right panel: In human cells, the work of a number of laboratories has uncovered that the centralspindlin complex recruits CEP55, which in turn directly interacts with ALIX to recruit it to the midbody. ALIX directly interacts with the ESCRT-III subunit CHMP4B to promote cytokinetic abscission in human cells. Together, the work in Drosophila and human cells shows an evolutionarily conserved role for the centralspindlin complex in recruiting components of the abscission machinery to the midbody.

 

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 .

Published June 10, 2022 9:52 AM - Last modified June 17, 2022 1:41 PM