DUB-2 IS A MEMBER OF A NOVEL FAMILY OF CYTOKINE-INDUCIBLE DEUBIQUITINATING ENZYMES

Cytokines regulate cell growth by inducing the expression of specific target genes. We have recently identified a cytokine-inducible, immedi ate-early gene, DUB-1, that encodes a deubiquitinating enzyme with gro wth regulatory activity. In the current study, we have isolated a high ly related gene, DUB-2, that is induced by interleukin-2. The DUB-2 mR NA was induced in T cells as an immediate-early gene and was rapidly d own-regulated. Like DUB-1, the DUB-2 protein had deubiquitinating acti vity in vitro. When a conserved cysteine residue of DUB-2, required fo r ubiquitin-specific thiol protease activity, was mutated to serine (C 60S), deubiquitinating activity was abolished. DUB-1 and DUB-2 protein s are highly related throughout their primary amino acid sequence exce pt for a hypervariable region at their COOH terminus. Moreover, the DU B genes co-localize to a region of mouse chromosome 7, suggesting that they arose by a tandem duplication of an ancestral DUB gene. Addition al DUB genes co-localize to this region, suggesting a larger family of cytokine-inducible DUB enzymes. We propose that different cytokines i nduce specific DUB genes. Each induced DUB enzyme thereby regulates th e degradation or the ubiquitination state of an unknown growth regulat ory factor, resulting in a cytokine-specific growth response.