title: IDOL stimulates clathrin-independent endocytosis and multivesicular body-mediated lysosomal degradation of the low-density lipoprotein receptor.
abstract: The low-density lipoprotein receptor (LDLR) is a critical determinant of plasma cholesterol levels that internalizes lipoprotein cargo via clathrin-mediated endocytosis. Here, we show that the E3 ubiquitin ligase IDOL stimulates a previously unrecognized, clathrin-independent pathway for LDLR internalization. Real-time single-particle tracking and electron microscopy reveal that IDOL is recruited to the plasma membrane by LDLR, promotes LDLR internalization in the absence of clathrin or caveolae, and facilitates LDLR degradation by shuttling it into the multivesicular body (MVB) protein-sorting pathway. The IDOL-dependent degradation pathway is distinct from that mediated by PCSK9 as only IDOL employs ESCRT (endosomal-sorting complex required for transport) complexes to recognize and traffic LDLR to lysosomes. Small interfering RNA (siRNA)-mediated knockdown of ESCRT-0 (HGS) or ESCRT-I (TSG101) components prevents IDOL-mediated LDLR degradation. We further show that USP8 acts downstream of IDOL to deubiquitinate LDLR and that USP8 is required for LDLR entry into the MVB pathway. These results provide key mechanistic insights into an evolutionarily conserved pathway for the control of lipoprotein receptor expression and cellular lipid uptake.
authors: Howard Hughes Medical Institute, USA.
authors: Elena
authors: E
authors: Scotti
authors: Martino
authors: M
authors: Calamai
authors: Chris N
authors: CN
authors: Goulbourne
authors: Li
authors: L
authors: Zhang
authors: Cynthia
authors: C
authors: Hong
authors: Ron R
authors: RR
authors: Lin
authors: Jinkuk
authors: J
authors: Choi
authors: Paul F
authors: PF
authors: Pilch
authors: Loren G
authors: LG
authors: Fong
authors: Peng
authors: P
authors: Zou
authors: Alice Y
authors: AY
authors: Ting
authors: Francesco S
authors: FS
authors: Pavone
authors: Stephen G
authors: SG
authors: Young
authors: Peter
authors: P
authors: Tontonoz
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics; D002460:Cell Line; D002966:Clathrin / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D004705:Endocytosis; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D057146:Multivesicular Bodies / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D021381:Protein Transport; D034622:RNA Interference; D034741:RNA, Small Interfering; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases; D014157:Transcription Factors / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000099177:Tsg101 Protein
chemical_list: D018797:Cell Cycle Proteins; D002966:Clathrin; D004268:DNA-Binding Proteins; D010450:Endopeptidases; D056827:Endosomal Sorting Complexes Required for Transport; D020662:Guanine Nucleotide Exchange Factors; D008077:Lipoproteins, LDL; D009687:Nuclear Proteins; D010750:Phosphoproteins; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D034741:RNA, Small Interfering; D011973:Receptors, LDL; D012697:Serine Endopeptidases; D014157:Transcription Factors; D043222:Ubiquitin Thiolesterase; D044767:Ubiquitin-Protein Ligases; D000099177:Tsg101 Protein; C573412:LDLR protein, human; C062521:RCC1 protein, human; C486696:STAMBP protein, human; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; C403126:MYLIP protein, human; C541534:USP8 protein, human; C472125:PCSK9 protein, human
references: Proc Natl Acad Sci U S A. 2011 Dec 13;108(50):20107-12
references: 22109552
references: Annu Rev Biophys Biomol Struct. 1997;26:373-99
references: 9241424
references: Annu Rev Cell Dev Biol. 2003;19:141-72
references: 14570567
references: Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2760-5
references: 15701692
references: J Biol Chem. 2004 Nov 19;279(47):48865-75
references: 15358785
references: Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2766-71
references: 15701696
references: Nat Rev Mol Cell Biol. 2000 Nov;1(2):153-6
references: 11253369
references: Cell Metab. 2008 Oct;8(4):310-7
references: 18840361
references: J Lipid Res. 2005 Jun;46(6):1312-9
references: 15741654
references: Dev Cell. 2006 Jun;10(6):839-50
references: 16740485
references: Science. 1976 Jan 16;191(4223):150-4
references: 174194
references: J Biol Chem. 2009 Oct 16;284(42):28856-64
references: 19635789
references: Exp Cell Res. 2008 Feb 15;314(4):801-13
references: 18031739
references: J Cell Biol. 1998 May 18;141(4):905-15
references: 9585410
references: J Biol Chem. 2011 Aug 26;286(34):30190-9
references: 21734303
references: Curr Opin Cell Biol. 2008 Feb;20(1):4-11
references: 18222686
references: Biophys J. 2007 May 15;92(10):3706-18
references: 17293395
references: IEEE Trans Image Process. 2005 Sep;14(9):1384-95
references: 16190473
references: Mol Biol Cell. 2006 Oct;17(10):4300-17
references: 16870701
references: J Clin Invest. 2006 Nov;116(11):2995-3005
references: 17080197
references: Genes Dev. 2011 Jun 15;25(12):1262-74
references: 21685362
references: J Cell Biol. 2003 Aug 4;162(3):435-42
references: 12900395
references: Biochem Biophys Res Commun. 2008 Oct 10;375(1):69-73
references: 18675252
references: J Cell Sci. 2012 Jan 15;125(Pt 2):265-75
references: 22357968
references: J Biol Chem. 2007 Mar 30;282(13):9805-9812
references: 17261583
references: Mol Biol Cell. 2003 Aug;14(8):3254-65
references: 12925761
references: Nat Neurosci. 2001 Mar;4(3):253-60
references: 11224541
references: J Virol. 2001 Nov;75(22):11166-77
references: 11602756
references: Cell. 1997 May 2;89(3):331-40
references: 9150132
references: J Biol Chem. 2012 Apr 13;287(16):12602-11
references: 22378787
references: Nat Cell Biol. 2011 Dec 22;14(1):38-45
references: 22193162
references: J Cell Sci. 2009 Jul 1;122(Pt 13):2163-6
references: 19535731
references: Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12050-5
references: 11593015
references: J Lipid Res. 2007 Jul;48(7):1488-98
references: 17449864
references: J Cell Biol. 1990 Dec;111(6 Pt 2):2931-8
references: 2148564
references: J Cell Biol. 1986 Feb;102(2):500-9
references: 2868013
references: J Cell Biol. 2003 Sep 1;162(5):909-18
references: 12952941
references: J Lipid Res. 2009 Apr;50 Suppl:S172-7
references: 19020338
references: J Biol Chem. 2006 May 5;281(18):12618-24
references: 16520378
references: Science. 2006 Sep 15;313(5793):1591-4
references: 16973870
references: J Lipid Res. 2012 Sep;53(9):1932-43
references: 22764087
references: Nature. 1997 Aug 14;388(6643):629-30
references: 9262394
references: Nat Protoc. 2006;1(6):2628-34
references: 17406518
references: Nature. 2009 Mar 26;458(7237):445-52
references: 19325624
references: Nature. 2007 Oct 11;449(7163):735-9
references: 17928861
references: J Biol Chem. 2008 Jan 25;283(4):2363-72
references: 18039658
references: J Cell Biol. 2010 Dec 27;191(7):1381-93
references: 21187331
references: J Lipid Res. 2010 Sep;51(9):2655-63
references: 20562239
references: J Biol Chem. 2008 Feb 15;283(7):4314-22
references: 18056712
references: J Struct Biol. 2005 Aug;151(2):182-95
references: 16043363
references: J Biol Chem. 2003 Apr 4;278(14):12513-21
references: 12551915
references: Mol Cell Biol. 2011 May;31(9):1885-93
references: 21343340
references: ACS Chem Biol. 2011 Apr 15;6(4):308-13
references: 21194239
references: J Biol Chem. 2010 Jun 25;285(26):19720-6
references: 20427281
references: Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):2069-74
references: 15677715
references: Traffic. 2007 Jun;8(6):718-32
references: 17461796
references: Nat Rev Mol Cell Biol. 2007 May;8(5):355-68
references: 17450176
references: J Biol Chem. 2007 Oct 19;282(42):30929-37
references: 17711858
references: J Cell Sci. 2009 Jun 1;122(Pt 11):1713-21
references: 19461071
references: Cell. 1984 Jun;37(2):577-85
references: 6327078
references: J Cell Biol. 2005 Jul 4;170(1):127-39
references: 15998804
references: Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11603-7
references: 7903453
references: Science. 2009 Jul 3;325(5936):100-4
references: 19520913
references: Cell Struct Funct. 2007;31(2):159-72
references: 17159328
references: Science. 1986 Apr 4;232(4746):34-47
references: 3513311
references: Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13332-7
references: 14597718
references: J Neurosci. 2009 Jun 17;29(24):7639-48
references: 19535575
references: Cell. 1983 Mar;32(3):941-51
references: 6299582
references: Curr Biol. 2006 Jan 24;16(2):160-5
references: 16431367
references: J Biol Chem. 2006 Feb 24;281(8):5094-105
references: 16371348