Monoubiquitylation promotes mitochondrial p53 translocation

EMBO J. 2007 Feb 21;26(4):923-34. doi: 10.1038/sj.emboj.7601560. Epub 2007 Feb 1.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / physiology*
  • Camptothecin
  • Cell Line, Tumor
  • Cytoplasm / metabolism
  • Endopeptidases / metabolism
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Mitochondria / metabolism*
  • Mitochondria / physiology
  • Models, Biological*
  • Protein Transport / physiology
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitin / metabolism*
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Peptidase 7

Substances

  • Tumor Suppressor Protein p53
  • Ubiquitin
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Endopeptidases
  • USP7 protein, human
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Peptidase 7
  • Camptothecin