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Abstract

We have isolated Ubp41, a ubiquitin-specific protease, in a screen for proapoptotic genes. We found that overexpression of Ubp41 is sufficient to elicit all features of apoptosis in human cells. In contrast, an enzymatically defective UBP41 mutant and homologous ubiquitin-processing protease family members did not significantly induce cell death. Overexpression of Ubp41 resulted in a strong deubiquitination of a broad range of proteins, but surprisingly did not lead to a stabilization of protein substrates known to be regulated by the ubiquitin- proteasome system such as the cell cycle factors p21 and p27. Hence, in contrast to the proteasome inhibitor MG132, Ubp41 overexpression did not arrest cells in G2/M. Rather, overexpression of hUbp41 seems to interfere with the ubiquitin- system and to cause the activation of apoptosis pathways by stabilizing specific substrates. Hence, for the first time we found that a member of the deubiquitinating enzymes has a direct proapoptotic activity additionally tightening the connection between apoptosis and the ubiquitin-proteasome system.