Abstract
Cullins (CULs) are a core component of cullin-RING E3 ubiquitin ligases (CRLs), which regulate the degradation, function, and subcellular trafficking of proteins. CULs are post-translationally regulated through neddylation, a process that conjugates the ubiquitin-like modifier protein neural precursor cell expressed developmentally downregulated protein 8 (NEDD8) to target cullins, as well as non-cullin proteins. Counteracting neddylation is the deneddylase, COP9 signalosome (CSN), which removes NEDD8 from target proteins. Recent comparative genomics studies revealed that CRLs and the CSN are highly conserved in Amoebozoa. A well-studied representative of Amoebozoa, the social amoeba Dictyostelium discoideum, has been used for close to 100 years as a model organism for studying conserved cellular and developmental processes owing to its unique life cycle comprised of unicellular and multicellular phases. The organism is also recognized as an exceptional model system for studying cellular processes impacted by human diseases, including but not limited to, cancer and neurodegeneration. Recent work shows that the neddylation inhibitor, MLN4924 (Pevonedistat), inhibits growth and multicellular development in D. discoideum, which supports previous work that revealed the cullin interactome in D. discoideum and the roles of cullins and the CSN in regulating cellular and developmental processes during the D. discoideum life cycle. Here, we review the roles of cullins, neddylation, and the CSN in D. discoideum to guide future work on using this biomedical model system to further explore the evolutionarily conserved functions of cullins and neddylation.
Highlights
THE LIFE CYCLE OF DICTYOSTELIUM DISCOIDEUMD. discoideum belongs to a clade within the Amoebozoan known as the social amoebae, a term coined by Bonner (1949) after observing that unicellular D. discoideum amoebae could develop into multicellular fruiting bodies when prompted by starvation
Recent comparative genomics studies revealed that cullin-RING E3 ubiquitin ligases (CRLs) and the COP9 signalosome (CSN) are highly conserved in Amoebozoa
In D. discoideum, CRL-mediated ubiquitination regulates complex processes associated with growth and multicellular development (Figure 6)
Summary
D. discoideum belongs to a clade within the Amoebozoan known as the social amoebae, a term coined by Bonner (1949) after observing that unicellular D. discoideum amoebae could develop into multicellular fruiting bodies when prompted by starvation. The other ~20% differentiate into pre-stalk cells and become non-reproductive cells that comprise the stalk and two other segments of the fruiting body. These two other segments are composed of differentiated cells derived from the same cell type as the stalk cells and are referred to as the cup and basal disk cells (they constitute both the cup and basal structures of the fruiting body, respectively; Chen and Schaap, 2016). The D. discoideum life cycle highlights the evolution of many processes required for multicellular development, including but not limited to, cell– cell communication, cell–cell adhesion, and differentiation
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