The P-body Component USP52/PAN2 Is a Novel Regulator of HIF1A mRNA Stability

Biochem J. 2013 Apr 15;451(2):185-94. doi: 10.1042/BJ20130026.

Abstract

HIF1A (hypoxia-inducible factor 1α) is the master regulator of the cellular response to hypoxia and is implicated in cancer progression. Whereas the regulation of HIF1A protein in response to oxygen is well characterized, less is known about the fate of HIF1A mRNA. In the present study, we have identified the pseudo-DUB (deubiquitinating enzyme)/deadenylase USP52 (ubiquitin-specific protease 52)/PAN2 [poly(A) nuclease 2] as an important regulator of the HIF1A-mediated hypoxic response. Depletion of USP52 reduced HIF1A mRNA and protein levels and resulted in reduced expression of HIF1A-regulated hypoxic targets due to a 3'-UTR (untranslated region)-dependent poly(A)-tail-length-independent destabilization in HIF1A mRNA. MS analysis revealed an association of USP52 with several P-body (processing body) components and we confirmed further that USP52 protein and HIF1A mRNA co-localized with cytoplasmic P-bodies. Importantly, P-body dispersal by knockdown of GW182 or LSM1 resulted in a reduction of HIF1A mRNA levels. These data uncover a novel role for P-bodies in regulating HIF1A mRNA stability, and demonstrate that USP52 is a key component of P-bodies required to prevent HIF1A mRNA degradation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • AU Rich Elements
  • Autoantigens / genetics
  • Autoantigens / metabolism
  • Cell Hypoxia / genetics
  • Cell Line
  • Cytoplasmic Structures / genetics
  • Cytoplasmic Structures / metabolism*
  • Exoribonucleases / genetics
  • Exoribonucleases / metabolism*
  • Gene Knockdown Techniques
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Poly A
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • RNA Stability*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism

Substances

  • 3' Untranslated Regions
  • Autoantigens
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • LSM1 protein, human
  • Proto-Oncogene Proteins
  • RNA-Binding Proteins
  • autoantigen GW182, human
  • Poly A
  • Exoribonucleases
  • PAN2 protein, human