The de-ubiquitinylating enzyme, USP2, is associated with the circadian clockwork and regulates its sensitivity to light

PLoS One. 2011;6(9):e25382. doi: 10.1371/journal.pone.0025382. Epub 2011 Sep 23.

Abstract

We have identified a novel component of the circadian clock that regulates its sensitivity to light at the evening light to dark transition. USP2 (Ubiquitin Specific Protease 2), which de-ubiquitinylates and stabilizes target proteins, is rhythmically expressed in multiple tissues including the SCN. We have developed a knockout model of USP2 and found that exposure to low irradiance light at ZT12 increases phase delays of USP2(-/-) mice compared to wildtype. We additionally show that USP2b is in a complex with several clock components and regulates the stability and turnover of BMAL1, which in turn alters the expression of several CLOCK/BMAL1 controlled genes. Rhythmic expression of USP2 in the SCN and other tissues offers a new level of control of the clock machinery through de-ubiqutinylation and suggests a role for USP2 during circadian adaptation to environmental day length changes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ARNTL Transcription Factors / genetics
  • ARNTL Transcription Factors / metabolism
  • Animals
  • Blotting, Western
  • CLOCK Proteins / genetics
  • CLOCK Proteins / metabolism
  • Cell Line
  • Circadian Rhythm / genetics
  • Circadian Rhythm / radiation effects
  • Endopeptidases / genetics
  • Endopeptidases / metabolism*
  • Female
  • Humans
  • Immunoprecipitation
  • Light*
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • NIH 3T3 Cells
  • Period Circadian Proteins / genetics
  • Period Circadian Proteins / metabolism
  • Polymerase Chain Reaction
  • Retina / metabolism
  • Suprachiasmatic Nucleus / metabolism
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Proteases

Substances

  • ARNTL Transcription Factors
  • Per1 protein, mouse
  • Period Circadian Proteins
  • CLOCK Proteins
  • Endopeptidases
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Proteases
  • Usp2 protein, mouse