title: The Deubiquitylase USP2 Regulates the LDLR Pathway by Counteracting the E3-Ubiquitin Ligase IDOL.
abstract: BACKGROUND
  The low-density lipoprotein (LDL) receptor (LDLR) is a central determinant of circulating LDL-cholesterol and as such subject to tight regulation. Recent studies and genetic evidence implicate the inducible degrader of the LDLR (IDOL) as a regulator of LDLR abundance and of circulating levels of LDL-cholesterol in humans. Acting as an E3-ubiquitin ligase, IDOL promotes ubiquitylation and subsequent lysosomal degradation of the LDLR. Consequently, inhibition of IDOL-mediated degradation of the LDLR represents a potential strategy to increase hepatic LDL-cholesterol clearance.
  
  
  OBJECTIVE
  To establish whether deubiquitylases counteract IDOL-mediated ubiquitylation and degradation of the LDLR.
  
  
  RESULTS
  Using a genetic screening approach, we identify the ubiquitin-specific protease 2 (USP2) as a post-transcriptional regulator of IDOL-mediated LDLR degradation. We demonstrate that both USP2 isoforms, USP2-69 and USP2-45, interact with IDOL and promote its deubiquitylation. IDOL deubiquitylation requires USP2 enzymatic activity and leads to a marked stabilization of IDOL protein. Paradoxically, this also markedly attenuates IDOL-mediated degradation of the LDLR and the ability of IDOL to limit LDL uptake into cells. Conversely, loss of USP2 reduces LDLR protein in an IDOL-dependent manner and limits LDL uptake. We identify a tri-partite complex encompassing IDOL, USP2, and LDLR and demonstrate that in this context USP2 promotes deubiquitylation of the LDLR and prevents its degradation.
  
  
  CONCLUSIONS
  Our findings identify USP2 as a novel regulator of lipoprotein clearance owing to its ability to control ubiquitylation-dependent degradation of the LDLR by IDOL.
authors.affiliation: From the Department of Medical Biochemistry, Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands (J.K.N., V.S., R.A.T., B.D., N.Z.); and Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom (C.H., S.U.).
authors.forename: Jessica Kristine
authors.initials: JK
authors.lastname: Nelson
authors.affiliation: From the Department of Medical Biochemistry, Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands (J.K.N., V.S., R.A.T., B.D., N.Z.); and Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom (C.H., S.U.).
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Sorrentino
authors.affiliation: From the Department of Medical Biochemistry, Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands (J.K.N., V.S., R.A.T., B.D., N.Z.); and Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom (C.H., S.U.).
authors.forename: Rossella
authors.initials: R
authors.lastname: Avagliano Trezza
authors.affiliation: From the Department of Medical Biochemistry, Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands (J.K.N., V.S., R.A.T., B.D., N.Z.); and Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom (C.H., S.U.).
authors.forename: Claire
authors.initials: C
authors.lastname: Heride
authors.affiliation: From the Department of Medical Biochemistry, Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands (J.K.N., V.S., R.A.T., B.D., N.Z.); and Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom (C.H., S.U.).
authors.forename: Sylvie
authors.initials: S
authors.lastname: Urbe
authors.affiliation: From the Department of Medical Biochemistry, Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands (J.K.N., V.S., R.A.T., B.D., N.Z.); and Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom (C.H., S.U.).
authors.forename: Ben
authors.initials: B
authors.lastname: Distel
authors.affiliation: From the Department of Medical Biochemistry, Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands (J.K.N., V.S., R.A.T., B.D., N.Z.); and Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom (C.H., S.U.). n.zelcer@amc.uva.nl.
authors.forename: Noam
authors.initials: N
authors.lastname: Zelcer
mesh_terms: D000818:Animals; D008078:Cholesterol, LDL / Q000378:metabolism*; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004795:Enzyme Stability; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D018345:Mice, Knockout; D009097:Multienzyme Complexes; D011485:Protein Binding; D059748:Proteolysis; D034622:RNA Interference; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D043222:Ubiquitin Thiolesterase; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D008078:Cholesterol, LDL; C573412:LDLR protein, human; D009097:Multienzyme Complexes; D011973:Receptors, LDL; C403126:MYLIP protein, human; C542022:Mylip protein, mouse; D044767:Ubiquitin-Protein Ligases; D010450:Endopeptidases; C108665:USP2 protein, human; D043222:Ubiquitin Thiolesterase
keywords: E3 ubiquitin ligase; LDL cholesterol; LDL receptors; MYLIP/IDOL; USP2; ubiquitin