The ubiquitin ligase Cullin5 SOCS2 regulates NDR1/STK38 stability and NF-κB transactivation

Sci Rep. 2017 Feb 20;7:42800. doi: 10.1038/srep42800.

Abstract

SOCS2 is a pleiotropic E3 ligase. Its deficiency is associated with gigantism and organismal lethality upon inflammatory challenge. However, mechanistic understanding of SOCS2 function is dismal due to our unawareness of its protein substrates. We performed a mass spectrometry based proteomic profiling upon SOCS2 depletion and yield quantitative data for ~4200 proteins. Through this screen we identify a novel target of SOCS2, the serine-threonine kinase NDR1. Over-expression of SOCS2 accelerates turnover, while its knockdown stabilizes, endogenous NDR1 protein. SOCS2 interacts with NDR1 and promotes its degradation through K48-linked ubiquitination. Functionally, over-expression of SOCS2 antagonizes NDR1-induced TNFα-stimulated NF-κB activity. Conversely, depletion of NDR1 rescues the effect of SOCS2-deficiency on TNFα-induced NF-κB transactivation. Using a SOCS2-/- mice model of colitis we show that SOCS2-deficiency is pro-inflammatory and negatively correlates with NDR1 and nuclear p65 levels. Lastly, we provide evidence to suggest that NDR1 acts as an oncogene in prostate cancer. To the best of our knowledge, this is the first report of an identified E3 ligase for NDR1. These results might explain how SOCS2-deficiency leads to hyper-activation of NF-κB and downstream pathological implications and posits that SOCS2 induced degradation of NDR1 may act as a switch in restricting TNFα-NF-κB pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Colitis / genetics
  • Colitis / metabolism*
  • Disease Models, Animal
  • Enzyme Stability
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Male
  • Mass Spectrometry
  • Mice
  • NF-kappa B / metabolism*
  • Prostatic Neoplasms / metabolism*
  • Protein-Serine-Threonine Kinases / chemistry*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteomics / methods*
  • Suppressor of Cytokine Signaling Proteins / deficiency
  • Suppressor of Cytokine Signaling Proteins / metabolism*
  • Transcriptional Activation
  • Tumor Necrosis Factor-alpha / metabolism
  • Ubiquitination

Substances

  • NF-kappa B
  • SOCS2 protein, human
  • Suppressor of Cytokine Signaling Proteins
  • TNF protein, human
  • Tumor Necrosis Factor-alpha
  • Protein-Serine-Threonine Kinases
  • STK38 protein, human