Bile acid signaling pathways increase stability of Small Heterodimer Partner (SHP) by inhibiting ubiquitin–proteasomal degradation

  1. Ji Miao1,
  2. Zhen Xiao2,
  3. Deepthi Kanamaluru1,
  4. Gyesik Min1,
  5. Peter M. Yau3,
  6. Timothy D. Veenstra2,
  7. Ewa Ellis4,
  8. Steve Strom4,
  9. Kelly Suino-Powell5,
  10. H. Eric Xu5 and
  11. Jongsook Kim Kemper1,6
  1. 1Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA;
  2. 2Laboratory of Proteomics and Analytical Technologies, Advanced Technology Program, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, Maryland 21712, USA;
  3. 3Carver Biotechnology Center, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA;
  4. 4Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA;
  5. 5Laboratory of Structure Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA

    Abstract

    Small Heterodimer Partner (SHP) inhibits activities of numerous transcription factors involved in diverse biological pathways. As an important metabolic regulator, SHP plays a key role in maintaining cholesterol and bile acid homeostasis by inhibiting cholesterol conversion to bile acids. While SHP gene induction by increased bile acids is well established, whether SHP activity is also modulated remains unknown. Here, we report surprising findings that SHP is a rapidly degraded protein via the ubiquitin–proteasomal pathway and that bile acids or bile acid-induced intestinal fibroblast growth factor 19 (FGF19) increases stability of hepatic SHP by inhibiting proteasomal degradation in an extracellular signal-regulated kinase (ERK)-dependent manner. SHP was ubiquitinated at Lys122 and Lys123, and mutation of these sites altered its stability and repression activity. Tandem mass spectrometry revealed that upon bile acid treatment, SHP was phosphorylated at Ser26, within an ERK motif in SHP, and mutation of this site dramatically abolished SHP stability. Surprisingly, SHP stability was abnormally elevated in ob/ob mice and diet-induced obese mice. These results demonstrate an important role for regulation of SHP stability in bile acid signaling in normal conditions, and that abnormal stabilization of SHP may be associated with metabolic disorders, including obesity and diabetes.

    Keywords

    Footnotes

    | Table of Contents

    Life Science Alliance