Ubiquitin-specific protease 2-69 in macrophages potentially modulates metainflammation

FASEB J. 2013 Dec;27(12):4940-53. doi: 10.1096/fj.13-233528. Epub 2013 Sep 4.


Macrophages play a critical role in chronic inflammation and metabolic diseases. We identified a longer splice variant of ubiquitin specific protease (USP) 2-69 as a novel molecule that modulates pathways implicated in metabolic disorders. Expression levels of aP2/FABP4 and PAI-1/SERPINE1 genes were increased by 4- and 1.8-fold, respectively, after short hairpin RNA-mediated knockdown (KD) of the USP2 gene, and such expression was alleviated by overexpression of USP2-69 in human myeloid cell lines. Supernatants derived from USP2-KD cells induced IL6 (∼6-fold) and SAA3 (∼15-fold) in 3T3-L1 adipocytes to suggest the anti-inflammatory properties of USP2. In addition, we observed a 30% decrease in the number of macrophages in mesenteric adipose tissue derived from USP2-69 transgenic mice fed a high-fat diet for 14 wk compared with that in their C57BL/6 littermates (P<0.01), which was consistent with a ∼40% decrease in transcription of aP2 and PAI-1. The aP2 locus exhibited elevated chromatin accessibility (>2.1-fold), methylation of histone H3 lysine 4 (>4.5-fold), and acetylation of histone H4 (>2.5-fold) in USP2-KD cells. Transfection of isopeptidase-mutated USP2-69 did not alter chromatin conformation on the aP2 locus in USP2-KD cells. Our results suggest that USP2-69 suppresses meta-inflammatory molecules involved in the development of type-2 diabetes.

Keywords: aP2; diabetes; epigenetic control.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism
  • Animals
  • Cell Line
  • Chromatin / metabolism
  • Chromatin Assembly and Disassembly*
  • Endopeptidases / genetics*
  • Endopeptidases / metabolism
  • Epigenesis, Genetic
  • Histones / metabolism
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Macrophages / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Cells / metabolism
  • Plasminogen Activator Inhibitor 1 / genetics
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Serum Amyloid A Protein / genetics
  • Serum Amyloid A Protein / metabolism
  • Transcription Factor AP-2 / genetics
  • Transcription Factor AP-2 / metabolism
  • Transcription, Genetic*
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Proteases / genetics*
  • Ubiquitin-Specific Proteases / metabolism


  • Chromatin
  • Histones
  • Interleukin-6
  • Plasminogen Activator Inhibitor 1
  • Serum Amyloid A Protein
  • Transcription Factor AP-2
  • Endopeptidases
  • USP2 protein, human
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Proteases
  • Usp2 protein, mouse