De-ubiquitinating proteases USP2a and USP2c cause apoptosis by stabilising RIP1.
Dynamic ubiquitination impacts on the degradation of proteins by the proteasome as well as on their effects as signalling factors. Of the many cellular responses that are regulated by changes in ubiquitination, apoptosis has garnered special attention. We have found that USP2a and USP2c, two isoforms of the ubiquitin-specific protease USP2, cause cell death upon ectopic expression. We show that both USP2 isoforms can control the ubiquitination status of many proteins but from a panel of potential targets only the protein level of RIP1 was increased by these enzymes. This effect is responsible for the activity of USP2a and USP2c to cause cell death. Both enzymes likewise de-ubiquitinate TRAF2, a ubiquitin-ligase in the TNFR1 complex. Whilst this and the similar sub-cellular localisations of both enzyme isoforms indicate a substantial overlap of activities, inactivation by RNAi revealed that only the knock-down of USP2c resulted in apoptosis, whilst targeting USP2a did not have any consequence on the cells' survival. Consequently, we focussed our studies on USP2a and found that TRAF2 inhibits USP2a's effect on K48- but not on K63-linked ubiquitin chains. Hence, the ratio between USP2a and TRAF2 protein levels determines the cells' sensitivity to cell death.
Division of Experimental Medicine, Imperial College, London, UK.
Anne-Laure
AL
Mahul-Mellier
Christoph
C
Datler
Evangelos
E
Pazarentzos
Bevan
B
Lin
Wanwisa
W
Chaisaklert
Ghada
G
Abuali
Stefan
S
Grimm
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism / Q000502:physiology; D051379:Mice; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism*; D055550:Protein Stability; D021381:Protein Transport; D059748:Proteolysis; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000378:metabolism*; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D043222:Ubiquitin Thiolesterase; D057149:Ubiquitinated Proteins / Q000378:metabolism
C119724:AGFG1 protein, human; D007527:Isoenzymes; D028861:Nuclear Pore Complex Proteins; D016601:RNA-Binding Proteins; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D057149:Ubiquitinated Proteins; D010450:Endopeptidases; C108665:USP2 protein, human; D043222:Ubiquitin Thiolesterase