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UBP41 Is a Proapoptotic Ubiquitin-specific Protease¹

Max-Planck-Institute for Biochemistry, 82152 Martinsried, Germany

We have isolated Ubp41, a ubiquitin-specific protease, in a screen for proapoptoticgenes. 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.

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