Proposed scheme for the effect of Ubal on Ub-dependent proteolysis of Hb α-subunits in β-thalassemic hemolysates. Ub molecules are conjugated to the α-chain or α-globin substrates. Without Ubal, there are few conjugates and most are only sparsely ubiquitinated, in part because of ongoing deubiquitination by isopeptidase(s). These conjugates are poorly degraded by the 26S proteasome. Deubiquitination is inhibited by low concentrations (≤1 μmol/L) of Ubal. This results in more highly ubiquitinated conjugates (either from ubiquitination of multiple substrate lysines or from elaboration of polyUb chains, or both) that are more efficiently degraded by the 26S proteasome. Also, inhibition by Ubal of an “editing” isopeptidase within the 26S proteasome promotes degradation of even poorly ubiquitinated α-subunits.42 At higher levels, Ubal also blocks another isopeptidase(s) that leads to the accumulation of unanchored polyUb chains that inhibit processing of conjugates by the 26S proteasome.