Stimulation by interferons alters the composition of the proteolytic proteasome core [44] , tailoring its activity toward generation of peptide-MHC complexes for inspection by the immune system. Interferon treatment also results in enhanced modification of proteins by ISG15 -a factor that evolved in the vertebrate lineage, and whose origin thus coincides with that of the adaptive immune system. Interestingly, inhibition of the proteasome leads to rampant accumulation of ISG15-modified substrates [45] . While nothing is known about the molecular functions of ISG15, its structural relative FAT10 is a modifier that destines proteins for degradation by the proteasome [8] . We now have demonstrated that USP14 exhibits proteasome-associated isopeptidase activity toward ISG15. Could therefore ISG15 be a (co-)modifier of proteins destined for proteasomal degradation? We have found no evidence that USP14 markedly changes the amount of ISG15-modified substrates in cells (data not shown). However, USP14 is not a vital protease [30, 46] and its low catalytic turnover does not affect overall ubiquitin conjugation either [47] . A recent study suggests that USP14 might have a more complex role, by inhibiting the proteasome in addition to acting as a deubiquitinase [48] .