Host cell factors stimulate HIV-1 transcription by antagonizing substrate-binding function of Siah1 ubiquitin ligase to stabilize transcription elongation factor ELL2.
Animals
Binding Sites
Cell Line
Chlorocebus aethiops
HeLa Cells
Host Cell Factor C1
/ metabolism
Humans
Nuclear Proteins
/ chemistry
Protein Binding
Transcriptional Elongation Factors
/ metabolism
Ubiquitin-Protein Ligases
/ chemistry
Ubiquitination
tat Gene Products, Human Immunodeficiency Virus
/ metabolism
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
27 07 2020
27 07 2020
Historique:
accepted:
19
05
2020
revised:
12
05
2020
received:
26
11
2019
pubmed:
2
6
2020
medline:
17
9
2020
entrez:
2
6
2020
Statut:
ppublish
Résumé
The Siah1 and Siah2 ubiquitin ligases are implicated in diverse biological processes ranging from cellular stress responses, signaling to transcriptional regulation. A key substrate of Siah1 is ELL2, which undergoes proteolysis upon polyubiquitination. ELL2 stimulates transcriptional elongation and is a subunit of the Super Elongation Complex (SEC) essential for HIV-1 transactivation. Previously, multiple transcriptional and post-translational mechanisms are reported to control Siah's expression and activity. Here we show that the activity of Siah1/2 can also be suppressed by host cell factor 1 (HCF1), and the hitherto poorly characterized HCF2, which themselves are not degraded but can bind and block the substrate-binding domain (SBD) of Siah1/2 to prevent their autoubiquitination and trans-ubiquitination of downstream targets including ELL2. This effect stabilizes ELL2 and enhances the ELL2-SEC formation for robust HIV-1 transactivation. Thus, our study not only identifies HCF1/2 as novel activators of HIV-1 transcription through inhibiting Siah1 to stabilize ELL2, but also reveals the SBD of Siah1/2 as a previously unrecognized new target for HCF1/2 to exert this inhibition.
Identifiants
pubmed: 32479599
pii: 5849913
doi: 10.1093/nar/gkaa461
pmc: PMC7367184
doi:
Substances chimiques
ELL2 protein, human
0
Host Cell Factor C1
0
Nuclear Proteins
0
Transcriptional Elongation Factors
0
tat Gene Products, Human Immunodeficiency Virus
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
seven in absentia proteins
EC 2.3.2.27
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7321-7332Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.
Références
Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3510-5
pubmed: 14985507
Mol Cell. 2005 Aug 19;19(4):535-45
pubmed: 16109377
Breast Cancer Res. 2011 Feb 09;13(1):R19
pubmed: 21306611
Mol Cell. 2001 May;7(5):915-26
pubmed: 11389839
PLoS Pathog. 2019 Jan 15;15(1):e1007498
pubmed: 30645648
Mol Cell Biochem. 2011 Nov;357(1-2):209-15
pubmed: 21633900
Viruses. 2013 May 22;5(5):1272-91
pubmed: 23698399
Cell Host Microbe. 2011 Nov 17;10(5):426-35
pubmed: 22100159
Genes Dev. 2010 Jul 15;24(14):1479-84
pubmed: 20581084
Mol Cell. 2008 Mar 14;29(5):588-99
pubmed: 18249148
Neurotoxicology. 2018 Sep;68:212-221
pubmed: 29217406
Genes Nutr. 2013 Jan;8(1):69-78
pubmed: 22570175
Cell Host Microbe. 2017 Apr 12;21(4):507-517.e5
pubmed: 28407486
Biochim Biophys Acta Gene Regul Mech. 2017 Oct;1860(10):1037-1046
pubmed: 28843785
Front Pharmacol. 2018 Aug 03;9:857
pubmed: 30123132
Proc Natl Acad Sci U S A. 2013 Jan 8;110(2):E123-31
pubmed: 23251033
Mol Cell. 2012 May 11;46(3):325-34
pubmed: 22483617
Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13153-7
pubmed: 16141343
Nature. 1987 Dec 3-9;330(6147):489-93
pubmed: 2825027
Mol Cell. 2010 May 14;38(3):428-38
pubmed: 20471948
Mol Cell Biol. 2016 Feb 01;36(7):1194-205
pubmed: 26830226
Biochim Biophys Acta. 2015 May;1853(5):1174-81
pubmed: 25728284
Mol Cell Biol. 1999 Jan;19(1):724-32
pubmed: 9858595
Mol Cell. 2011 Nov 4;44(3):476-90
pubmed: 22055192
FEBS Lett. 2002 Feb 13;512(1-3):223-6
pubmed: 11852084
Mol Cells. 2015 Jun;38(6):562-72
pubmed: 25997740
Cell Rep. 2018 Jun 26;23(13):3741-3749
pubmed: 29949759
Biochim Biophys Acta. 2010 Mar-Apr;1799(3-4):257-65
pubmed: 19682612
PLoS One. 2014 Sep 09;9(9):e106547
pubmed: 25202994
Nucleic Acids Res. 2015 Jul 13;43(12):5868-79
pubmed: 26007649
J Neurosci. 2012 Nov 14;32(46):16391-401
pubmed: 23152621
Mol Cell. 2007 Jul 6;27(1):107-19
pubmed: 17612494
Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):E15-24
pubmed: 24367103
Science. 2013 Dec 6;342(6163):1235-9
pubmed: 24311690
Cell Biochem Biophys. 2013 Sep;67(1):15-24
pubmed: 23700162
RNA. 2003 Apr;9(4):493-501
pubmed: 12649500
Annu Rev Biochem. 2012;81:119-43
pubmed: 22404626
BMC Cancer. 2016 Jul 04;16:379
pubmed: 27377268
Mol Cell. 2010 May 14;38(3):439-51
pubmed: 20471949
J Cell Biol. 2003 Sep 1;162(5):899-908
pubmed: 12952940
Nucleic Acids Res. 2011 Mar;39(5):1880-93
pubmed: 21062812
Bull Cancer. 2018 Oct;105(10):873-883
pubmed: 30266288
J Virol. 2008 Dec;82(24):12291-303
pubmed: 18829756
Proc Natl Acad Sci U S A. 1988 Dec;85(24):9406-10
pubmed: 3200827