Ring finger protein 5 activates sterol regulatory element-binding protein 2 (SREBP2) to promote cholesterol biosynthesis via inducing polyubiquitination of SREBP chaperone SCAP.
Amino Acid Sequence
Cell Line
Cholesterol
/ biosynthesis
DNA-Binding Proteins
/ antagonists & inhibitors
Endoplasmic Reticulum
/ metabolism
Golgi Apparatus
/ metabolism
Humans
Intracellular Signaling Peptides and Proteins
/ chemistry
Membrane Proteins
/ chemistry
Mutagenesis, Site-Directed
Protein Binding
Protein Domains
RNA Interference
RNA, Small Interfering
/ metabolism
Sterol Regulatory Element Binding Protein 2
/ metabolism
Ubiquitin-Protein Ligases
/ antagonists & inhibitors
Ubiquitination
E3 ubiquitin ligase
SREBP chaperone (SCAP)
cholesterol
endoplasmic reticulum (ER)
lipid metabolism
polyubiquitin chain
post-translational modification (PTM)
ring finger protein 5 (RNF5)
sterol regulatory element-binding protein (SREBP)
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
20 03 2020
20 03 2020
Historique:
received:
10
11
2019
revised:
04
02
2020
pubmed:
15
2
2020
medline:
15
12
2020
entrez:
15
2
2020
Statut:
ppublish
Résumé
Sterol regulatory element-binding protein 2 (SREBP2) is the master transcription factor that regulates cholesterol metabolism. SREBP2 activation is regulated by SREBP chaperone SCAP. Here we show that ring finger protein 5 (RNF5), an endoplasmic reticulum-anchored E3 ubiquitin ligase, mediates the Lys-29-linked polyubiquitination of SCAP and thereby activates SREBP2. RNF5 knockdown inhibited SREBP2 activation and reduced cholesterol biosynthesis in human hepatoma cells, and RNF5 overexpression activated SREBP2. Mechanistic studies revealed that RNF5 binds to the transmembrane domain of SCAP and ubiquitinates the Lys-305 located in cytosolic loop 2 of SCAP. Moreover, the RNF5-mediated ubiquitination enhanced an interaction between SCAP luminal loop 1 and loop 7, a crucial event for SREBP2 activation. Notably, an overexpressed K305R SCAP variant failed to restore the SREBP2 pathway in SCAP-deficient cell lines. These findings define a new mechanism by which an ubiquitination-induced SCAP conformational change regulates cholesterol biosynthesis.
Identifiants
pubmed: 32054686
pii: S0021-9258(17)48783-7
doi: 10.1074/jbc.RA119.011849
pmc: PMC7086040
doi:
Substances chimiques
DNA-Binding Proteins
0
Intracellular Signaling Peptides and Proteins
0
Membrane Proteins
0
RNA, Small Interfering
0
SREBF2 protein, human
0
SREBP cleavage-activating protein
0
Sterol Regulatory Element Binding Protein 2
0
Cholesterol
97C5T2UQ7J
RNF5 protein, human
EC 2.3.2.27
Ubiquitin-Protein Ligases
EC 2.3.2.27
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3918-3928Informations de copyright
© 2020 Kuan et al.
Références
Compr Physiol. 2013 Jul;3(3):1191-212
pubmed: 23897684
J Biol Chem. 2016 Jun 10;291(24):12888-96
pubmed: 27068746
J Biol Chem. 2011 Apr 29;286(17):15022-31
pubmed: 21343306
Annu Rev Biochem. 2018 Jun 20;87:783-807
pubmed: 28841344
Proc Natl Acad Sci U S A. 2018 Dec 26;115(52):E12228-E12234
pubmed: 30530672
J Lipid Res. 2016 Aug;57(8):1564-73
pubmed: 27324795
Cell Chem Biol. 2017 Feb 16;24(2):207-217
pubmed: 28132894
Mol Cell. 2015 Apr 2;58(1):83-94
pubmed: 25752573
Cell Rep. 2018 Sep 18;24(12):3296-3311.e6
pubmed: 30232010
Cell. 2018 Sep 20;175(1):133-145.e15
pubmed: 30220454
Cancer Cell. 2015 Nov 9;28(5):569-581
pubmed: 26555173
Cell. 2002 Aug 23;110(4):489-500
pubmed: 12202038
Endocr Rev. 2004 Dec;25(6):947-70
pubmed: 15583024
Autophagy. 2019 Jul;15(7):1130-1149
pubmed: 30686098
Hepatology. 2014 Sep;60(3):844-57
pubmed: 24425205
Nat Commun. 2019 Apr 2;10(1):1492
pubmed: 30940817
Crit Rev Biochem Mol Biol. 2010 Jun;45(3):185-98
pubmed: 20482385
Cell. 2014 Nov 20;159(5):1212-1226
pubmed: 25416956
Mol Cell. 2003 Jan;11(1):25-33
pubmed: 12535518
Cancer Cell. 2015 Mar 9;27(3):354-69
pubmed: 25759021
J Biol Chem. 2018 Mar 16;293(11):4047-4055
pubmed: 29374057
J Biol Chem. 1999 Aug 27;274(35):24714-20
pubmed: 10455139
Cell Metab. 2017 Feb 7;25(2):412-427
pubmed: 28041958
Cell. 2006 Aug 11;126(3):571-82
pubmed: 16901789
J Lipid Res. 2018 Sep;59(9):1745-1750
pubmed: 29959181
Nat Commun. 2016 Jun 07;7:11792
pubmed: 27273569
Immunity. 2009 Mar 20;30(3):397-407
pubmed: 19285439
Immunity. 2014 Dec 18;41(6):919-33
pubmed: 25526307
J Biol Chem. 2005 Jul 1;280(26):25242-9
pubmed: 15866869
Elife. 2017 Oct 25;6:
pubmed: 29068315
J Biol Chem. 2017 Feb 17;292(7):3016-3028
pubmed: 28003358
Mol Cell. 2015 Apr 2;58(1):95-109
pubmed: 25752577
J Clin Invest. 2018 Jul 2;128(7):3129-3143
pubmed: 29715200
Cell Metab. 2008 Dec;8(6):512-21
pubmed: 19041766
Trends Biochem Sci. 2013 Sep;38(9):453-60
pubmed: 23870665
Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12753-8
pubmed: 12242332
Cell. 2015 Dec 17;163(7):1716-29
pubmed: 26686653
J Biol Chem. 2015 Aug 14;290(33):20565-79
pubmed: 26140926
Elife. 2018 Dec 13;7:
pubmed: 30543180
Cell Metab. 2005 Jun;1(6):379-91
pubmed: 16054087
J Biol Chem. 1999 Oct 1;274(40):28549-56
pubmed: 10497220
Mol Cell Biol. 2013 Oct;33(20):4095-105
pubmed: 23959799
Nature. 1997 Jun 5;387(6633):569-72
pubmed: 9177342