HSCARG downregulates NF-κB signaling by interacting with USP7 and inhibiting NEMO ubiquitination

Cell Death Dis. 2014 May 15;5(5):e1229. doi: 10.1038/cddis.2014.197.


Nuclear factor κB (NF-κB) signaling is a central pathway that participates in a variety of key processes, including immunity, inflammation, cell growth and differentiation. The activity of NF-κB is strictly regulated by a cluster of proteins, and modifications of these proteins either promote or suppress signal transduction at various steps. Here we demonstrated that HSCARG suppresses TNFα-stimulated NF-κB signaling under physiological conditions. We elucidated the detailed mechanism through which HSCARG inhibits NF-κB activation. HSCARG interacts with NEMO and suppresses polyubiquitination of NEMO by interacting with the deubiquitinase USP7. HSACRG attenuates its inhibitory effect on NEMO ubiquitination in USP7 knockdown cells, and inhibition of NEMO polyubiquitination by USP7 is impaired in HSCARG(-/-) cells as well. Moreover, we demonstrated that USP7 is a negative regulator of TNFα-stimulated NF-κB activity. Altogether, our data indicate that HSCARG and USP7 function in concert in inhibiting polyubiquination of NEMO, thus inhibiting NF-κB activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Down-Regulation
  • Gene Knockdown Techniques
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism*
  • NF-kappa B / metabolism*
  • RNA Interference
  • Signal Transduction*
  • Time Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transfection
  • Tumor Necrosis Factor-alpha / metabolism
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism*
  • Ubiquitin-Specific Peptidase 7
  • Ubiquitination


  • IKBKG protein, human
  • NF-kappa B
  • NMRAL1 protein, human
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • I-kappa B Kinase
  • USP7 protein, human
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Peptidase 7