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  • br Asb Proteins and Mitochondrial Function Mitochondria are


    Asb Proteins and Mitochondrial Function Mitochondria are intracellular organelles in eukaryotic aa-dutp synthesis and are the main sites of oxidative phosphorylation and ATP production. In addition, mitochondria serve as signal transduction docking stations in pyroptosis and regulate a plethora of processes through the release of metabolites and other constituents of the cytoplasm, including apoptosis and epithelial-to-mesenchymal transition [44]. Apart from Notch signaling, mitochondria also appear to be a principal target for Asb function. Human ASB9 provokes ubiquitination and degradation of the mitochondrial creatine kinase, which in turn leads to the loss of mitochondrial function and mitochondrial membrane potential, thus inhibiting cell growth 45, 46. The importance of this effect is illustrated by its remarkable specificity: using novel modeling strategies, the interaction between human ASB9 and creatine kinase has been precisely mapped and the results are in concordance with previous small-angle X-ray scattering [22]. Intriguingly, this modeling study reported that only the correctly docked creatine kinase-containing E3 ligase enables the close approach of ubiquitin to the creatine kinase substrate, constituting the first report at the atomic level describing ubiquitin transfer by a Cullin-RING E3 ligase [21]. It is perhaps counterintuitive that Asb9 can act as a negative regulator of cell growth through its effects on mitochondria, and this may be negative feedback on the effects of Asb on muscle compartment expansion. In support of this notion, an ASB9 variant lacking the SOCS domain (ASB9 ΔSOCS) is unable to induce mitochondrial dysfunction, aa-dutp synthesis showing that the fundamental mechanisms involved are similar to those observed in the regulation of Notch signaling.
    Concluding Remarks ASB proteins are a family of E3 ubiquitin ligases. Within this family, the six-ankyrin repeat domain-containing ASBs (ASB5, ASB9, ASB11, and ASB13) are a distinct group because they are evolutionarily the most ancient ASBs and show unusually high conservation (C. intestinalis and human ASB11 being >49% similar at the amino acid level). ASBs appear to act by modification of Notch signaling and mitochondrial function, whereas their most fascinating physiological and pathophysiological role is in the regulation of compartment size. The evidence for this is most strong for ASB9 and ASB11 because their effects on neuronal, muscle, and endoderm compartment size have been shown using overexpression strategies in vivo in zebrafish and in fish with attenuated action of these genes, as well as in overexpression experiments using human and murine neuronal and muscle precursors; limited gene expression studies also appear to support this evidence. For ASB5 and ASB13, fewer data are available, although in vitro studies in murine muscle myoblasts do suggest that these variants can support Notch signaling and compartment expansion, as do limited studies in zebrafish and expression studies in mice and humans. Important questions remain (see Outstanding Questions) and it is especially frustrating that no genetic murine models exist to dissect the function of these genes. Thus, this group of E3 ubiquitin ligases has been revealed to be both fascinating and highly relevant.
    Acknowledgment This research was financially supported by a China Scholarship Council PhD fellowship (File No. 2014 0822 0029) to P.L.