Bile acid signaling pathways increase stability of Small Heterodimer Partner (SHP) by inhibiting ubiquitin-proteasomal degradation.
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.
Miao
Ji
J
Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Xiao
Zhen
Z
Kanamaluru
Deepthi
D
Min
Gyesik
G
Yau
Peter M
PM
Veenstra
Timothy D
TD
Ellis
Ewa
E
Strom
Steve
S
Suino-Powell
Kelly
K
Xu
H Eric
HE
Kemper
Jongsook Kim
JK
D000818:Animals; D001647:Bile Acids and Salts / Q000502:physiology*; D045744:Cell Line, Tumor; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005765:Gastrointestinal Agents / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D055550:Protein Stability / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D054875:Ubiquitination / Q000187:drug effects
D001647:Bile Acids and Salts; D005765:Gastrointestinal Agents; D018160:Receptors, Cytoplasmic and Nuclear; C099713:nuclear receptor subfamily 0, group B, member 2; D002635:Chenodeoxycholic Acid; D005346:Fibroblast Growth Factors; D048049:Extracellular Signal-Regulated MAP Kinases; D046988:Proteasome Endopeptidase Complex; D008239:Lysine