Uba1, short for ubiquitin-like modifier activating enzyme 1, is an X-linked gene encoding one of the two ubiquitin E1 enzymes. It plays a pivotal role in initiating ubiquitination, a crucial post-translational modification. Ubiquitination is involved in numerous cellular processes such as protein degradation, signal transduction, and immune response regulation [2].

Somatic mutations in Uba1, especially those affecting methionine-41 (p.Met41), have been associated with VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. In patients, this often leads to a severe, treatment-refractory inflammatory syndrome in late adulthood, with features like fevers, cytopenias, characteristic vacuoles in precursor cells, and various inflammatory and hematologic conditions [1]. Knockout of the cytoplasmic Uba1 isoform homologue in zebrafish caused systemic inflammation, indicating its role in maintaining immune homeostasis [1].

In conclusion, Uba1 is essential for initiating ubiquitination, a process fundamental to multiple cellular functions. The discovery of its association with VEXAS syndrome through in vivo models like zebrafish has provided insights into the pathogenesis of this previously unrecognized hematoinflammatory disorder, highlighting the importance of Uba1 in autoinflammatory and hematologic diseases [1,2].