UBA1 dysfunction in VEXAS and cancer (IMAGE)
Caption
Figure 1: Conceptual representation of the differential effect of UBA1 mutations based on the degree of loss of function of ubiquitin E1 enzyme UBA1. (left panel) UBA1, an E1 enzyme, activates ubiquitin and subsequently transfers the activated ubiquitin to up to approximately 30 E2 enzymes with various efficiency. The displayed heatmap illustrates the variability in ubiquitin transfer efficiency (dark green: low efficiency, brown: high efficiency) of UBA1 wild type (first column), UBA1 partial loss of function (second column) and UBA1 total loss of function (third column). Wild type UBA1 and partial loss of function mutations affect the ubiquitin transfer efficiency of a subset of E2 enzymes, whereas a total loss of function of UBA1 leads to a complete loss of loading of ubiquitin to E2 enzymes solely dependent on UBA1. (right panel) At the E2/E3-substrate transfer step, the effect of UBA1 loss of function is mediated by the decrease of available ubiquitin-loaded E2 enzymes. In the case of partial loss of function mutations, ubiquitylation of substrates can be variable due to the differential impairment of ubiquitin transfer to the E2 enzymes, which may result in imbalance of regulator proteins and altered cell fate.
Credit
2024 Sakuma et al.
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