Identification of small PDZK1-associated protein, DD96/MAP17, as a regulator of PDZK1 and plasma high density lipoprotein levels.
Scavenger receptor class B, type I (SR-BI) is the high density lipoprotein (HDL) receptor essential for hepatic uptake of HDL cholesterol. SR-BI was shown to impact plasma HDL levels and be anti-atherogenic. Thus, the ability to regulate hepatic SR-BI may allow for the modulation of plasma HDL cholesterol and progression ... of atherosclerosis. However, regulation of SR-BI in liver is not well understood. Recently, the PDZ domain containing protein PDZK1 was shown to interact with SR-BI and may serve an essential role in SR-BI cell surface expression. Here we identify an in vivo PDZK1-interacting protein that we named small PDZK1-associated protein (SPAP; also known as DD96/MAP17). Unexpectedly, we found that hepatic overexpression of SPAP in mice resulted in liver deficiency of PDZK1. The absence of PDZK1 in SPAP transgenic mice resulted in a deficiency of SR-BI in liver and markedly increased plasma HDL. Metabolic labeling experiments showed that the proteasome plays a role in the turnover of newly synthesized PDZK1, but that SPAP overexpression in liver increased PDZK1 turnover in an alternate, proteasome-independent pathway. Thus, SPAP may be an endogenous regulator of cellular PDZK1 levels by regulating PDZK1 turnover.
Mesh Terms:
Acetylcysteine, Amino Acid Sequence, Animals, Antigens, CD36, Cholesterol, HDL, Chromatography, High Pressure Liquid, Cysteine Endopeptidases, Electrophoresis, Polyacrylamide Gel, Enzyme Inhibitors, Gene Expression, Gene Expression Regulation, Humans, Liver, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Molecular Sequence Data, Multienzyme Complexes, Neoplasm Proteins, Proteasome Endopeptidase Complex, Receptors, Immunologic, Receptors, Lipoprotein, Receptors, Scavenger, Scavenger Receptors, Class B, Transfection
Acetylcysteine, Amino Acid Sequence, Animals, Antigens, CD36, Cholesterol, HDL, Chromatography, High Pressure Liquid, Cysteine Endopeptidases, Electrophoresis, Polyacrylamide Gel, Enzyme Inhibitors, Gene Expression, Gene Expression Regulation, Humans, Liver, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Molecular Sequence Data, Multienzyme Complexes, Neoplasm Proteins, Proteasome Endopeptidase Complex, Receptors, Immunologic, Receptors, Lipoprotein, Receptors, Scavenger, Scavenger Receptors, Class B, Transfection
J. Biol. Chem.
Date: Aug. 01, 2003
PubMed ID: 12754212
View in: Pubmed Google Scholar
Download Curated Data For This Publication
11860
Switch View:
- Interactions 2