Monoubiquitylation promotes mitochondrial p53 translocation.
A major function of the p53 tumor suppressor is the induction of a pleiotropic apoptotic program in response to stress through transcription-dependent and -independent mechanisms. In particular, this includes a direct apoptotic role of p53 at the mitochondria. Stress-induced p53 translocation to the mitochondria with subsequent outer membrane permeabilization is a common early component in p53-mediated apoptosis in normal and transformed cells. However, the mechanism of p53 delivery to the mitochondria remains unknown. Here, we show that the cytoplasm contains a separate and distinct p53 pool that is the major source for p53 translocation to the mitochondria upon its stress-induced stabilization. Using various manipulations that enhance or diminish p53 ubiquitylation, our data provide evidence that Mdm2-mediated monoubiquitylation of p53 greatly promotes its mitochondrial translocation and thus its direct mitochondrial apoptosis. On the other hand, p53 does not require Mdm2 as a shuttler. Upon arrival at the mitochondria, our data suggest that p53 undergoes rapid deubiquitylation by mitochondrial HAUSP via a stress-induced mitochondrial p53-HAUSP complex. This generates the apoptotically active non-ubiquitylated p53. Taken together, we propose a novel model for mitochondrial p53 targeting, whereby a distinct cytoplasmic pool of stabilized monoubiquitylated p53, generated in resting cells by basal levels of Mdm2-type ligases, is subject to a binary switch from a fate of inactivation via subsequent polyubiquitylation and degradation in unstressed cells, to a fate of activation via mitochondrial trafficking.
Marchenko
Natasha D
ND
Department of Pathology, Stony Brook University, Stony Brook, New York, NY 11794-869, USA.
Wolff
Sonja
S
Erster
Susan
S
Becker
Kerstin
K
Moll
Ute M
UM
D017209:Apoptosis / Q000502:physiology*; D002166:Camptothecin; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008928:Mitochondria / Q000378:metabolism* / Q000502:physiology; D008954:Models, Biological; D021381:Protein Transport / Q000502:physiology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7
D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D010450:Endopeptidases; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7; D002166:Camptothecin