Abstract
Questions have been raised since the discovery of UBA6 and its significant coexistence with UBE1 in the ubiquitin–proteasome system (UPS). The facts that UBA6 has the dedicated E2 enzyme USE1 and the E1–E2 cascade can activate and transfer both ubiquitin and ubiquitin-like protein FAT10 have attracted a great deal of attention to the regulational mechanisms of the UBA6–USE1 cascade and to how FAT10 and ubiquitin differentiate with each other. This review recapitulates the latest advances in UBA6 and its bispecific UBA6–USE1 pathways for both ubiquitin and FAT10. The intricate networks of UBA6 and its interplays with ubiquitin and FAT10 are briefly reviewed, as are their individual and collective functions in diverse physiological conditions.
Highlights
Ubiquitination, the post-translational modulation of protein by ubiquitin (UB), plays an important role in almost all cellular functions in eukaryotes [1,2,3]
Protein can be rescued from degradation by the ubiquitin proteasome system (UPS, and in this review we refer to ubiquitin–proteasome system (UPS) as an abbreviation for both ubiquitin and the ubiquitin-like protein FAT10 proteasome system) through deubiquitinases (DUBs), which remove the ubiquitin from its substrates before degradation
The replacement of the C-terminal tetrapeptide from CYCI to LRLR, which contributes to the selectivity of ubiquitin and ISG15 for their cognate E1s, resulted in the loss of specificity of FAT10 loading to the E1 and E2 enzymes
Summary
Ubiquitination, the post-translational modulation of protein by ubiquitin (UB), plays an important role in almost all cellular functions in eukaryotes [1,2,3]. E2, the ubiquitin-conjugating enzyme, accepts the ubiquitin and forms the second thioester bond with its active Cys residue. Predominant K48 homogeneous ubiquitin chains can target the conjugated protein to the 26S proteasome for degradation whereas the second-most abundant chain type K63 ubiquitin chains present nonproteolytic functions in cell signaling [4,6]. UBA6 and UBE1 share common E2s and E3s for ubiquitin, both E1 enzymes have their dedicated E2s, which can direct ubiquitin towards distinct subsets of E3s and protein substrates. UBA6 and its specific E2 USE1 are the only E1 and E2 enzymes found in the FAT10-proteasome signaling pathway—another branch of the UPS system [12] All of this evidence points out a non-redundant role of UBA6 in the UPS. Studies in recent years found that UBA6 is associated with several diseases, which may help us understand its novel physiological functions
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