HUWE1 controls tristetraprolin proteasomal degradation by regulating its phosphorylation.
cell biology
e3 ligase
human
huwe1
immunology
inflammation
mouse
tristetraprolin
ubiquitin
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
24 03 2023
24 03 2023
Historique:
received:
01
09
2022
accepted:
26
02
2023
medline:
28
3
2023
entrez:
24
3
2023
pubmed:
25
3
2023
Statut:
epublish
Résumé
Tristetraprolin (TTP) is a critical negative immune regulator. It binds AU-rich elements in the untranslated-regions of many mRNAs encoding pro-inflammatory mediators, thereby accelerating their decay. A key but poorly understood mechanism of TTP regulation is its timely proteolytic removal: TTP is degraded by the proteasome through yet unidentified phosphorylation-controlled drivers. In this study, we set out to identify factors controlling TTP stability. Cellular assays showed that TTP is strongly lysine-ubiquitinated, which is required for its turnover. A genetic screen identified the ubiquitin E3 ligase HUWE1 as a strong regulator of TTP proteasomal degradation, which we found to control TTP stability indirectly by regulating its phosphorylation. Pharmacological assessment of multiple kinases revealed that HUWE1-regulated TTP phosphorylation and stability was independent of the previously characterized effects of MAPK-mediated S52/S178 phosphorylation. HUWE1 function was dependent on phosphatase and E3 ligase binding sites identified in the TTP C-terminus. Our findings indicate that while phosphorylation of S52/S178 is critical for TTP stabilization at earlier times after pro-inflammatory stimulation, phosphorylation of the TTP C-terminus controls its stability at later stages.
Identifiants
pubmed: 36961408
doi: 10.7554/eLife.83159
pii: 83159
pmc: PMC10038661
doi:
pii:
Substances chimiques
Tristetraprolin
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
Ubiquitin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Austrian Science Fund FWF
ID : P 33000
Pays : Austria
Informations de copyright
© 2023, Scinicariello et al.
Déclaration de conflit d'intérêts
SS, AS, MS, AS, IS, KH, RG, RK, KF, VB, AB, TC, PK, JZ, GV No competing interests declared
Références
Methods Cell Biol. 1994;43 Pt A:99-112
pubmed: 7823872
J Biol Chem. 1995 Oct 20;270(42):25266-72
pubmed: 7559666
Elife. 2018 May 31;7:
pubmed: 29848443
EMBO J. 2000 Dec 1;19(23):6517-26
pubmed: 11101524
Arch Biochem Biophys. 2002 Aug 15;404(2):279-84
pubmed: 12147266
J Biol Chem. 2011 Nov 4;286(44):38466-38477
pubmed: 21921033
Proc Natl Acad Sci U S A. 1989 Oct;86(20):7751-5
pubmed: 2554287
Nat Methods. 2020 Jul;17(7):708-716
pubmed: 32514112
J Virol. 2004 Jan;78(2):1006-11
pubmed: 14694132
J Immunol. 2009 Jul 15;183(2):1197-206
pubmed: 19542371
J Exp Med. 2003 Dec 1;198(11):1717-27
pubmed: 14638848
Mol Cell Biol. 2006 Mar;26(6):2408-18
pubmed: 16508015
Science. 2003 Jan 17;299(5605):408-11
pubmed: 12481023
FEBS Lett. 2015 Sep 14;589(19 Pt A):2552-60
pubmed: 26226424
FEBS J. 2020 May;287(10):1985-1999
pubmed: 31713291
Nucleic Acids Res. 2011 May;39(10):4373-86
pubmed: 21278420
J Proteome Res. 2019 Jan 4;18(1):535-541
pubmed: 30351950
Mol Cell Biol. 2001 Jan;21(1):51-60
pubmed: 11113180
Mol Cell Biol. 2006 Mar;26(6):2399-407
pubmed: 16508014
Annu Rev Biochem. 2018 Jun 20;87:697-724
pubmed: 29652515
Science. 1998 Aug 14;281(5379):1001-5
pubmed: 9703499
Nucleic Acids Res. 2015 Apr 20;43(7):e47
pubmed: 25605792
Mol Syst Biol. 2011 Dec 20;7:560
pubmed: 22186734
Front Immunol. 2020 Jul 07;11:1398
pubmed: 32733464
Nucleic Acids Res. 2016 Sep 6;44(15):7418-40
pubmed: 27220464
Biochimie. 2001 Mar-Apr;83(3-4):301-10
pubmed: 11295490
Immunity. 1996 May;4(5):445-54
pubmed: 8630730
Annu Rev Biochem. 1996;65:801-47
pubmed: 8811196
Nat Methods. 2007 Nov;4(11):923-5
pubmed: 17952086
Elife. 2017 Jun 21;6:
pubmed: 28635594
Mol Cell Biol. 2014 Dec 1;34(23):4315-28
pubmed: 25246635
J Immunol. 2015 Jul 1;195(1):265-76
pubmed: 26002976
J Exp Med. 2013 Aug 26;210(9):1675-84
pubmed: 23940256
Mol Cell Biol. 2003 Jun;23(11):3798-812
pubmed: 12748283
Mol Cell Biol. 2014 Oct 1;34(19):3579-93
pubmed: 25022756
EMBO J. 1998 Aug 17;17(16):4744-52
pubmed: 9707433
Genes Dev. 2005 Feb 1;19(3):351-61
pubmed: 15687258
J Immunol. 2019 Oct 15;203(8):2291-2300
pubmed: 31527197
Mol Syst Biol. 2016 May 13;12(5):868
pubmed: 27178967
J Proteome Res. 2011 Dec 2;10(12):5354-62
pubmed: 22073976
Mol Cell Biol. 2001 Sep;21(17):5778-89
pubmed: 11486017
Elife. 2023 Mar 24;12:
pubmed: 36961408
Genes Dev. 1999 Jul 1;13(13):1653-63
pubmed: 10398679
J Biol Chem. 1990 Mar 25;265(9):4789-92
pubmed: 2180950
Cell. 2014 Oct 9;159(2):440-55
pubmed: 25263330
Mol Cell Proteomics. 2014 Sep;13(9):2513-26
pubmed: 24942700
Mol Cell Biol. 1999 Jun;19(6):4311-23
pubmed: 10330172
Cell Rep. 2021 Jul 27;36(4):109421
pubmed: 34320342
Nat Struct Mol Biol. 2013 Jun;20(6):735-9
pubmed: 23644599
Mol Cell Biol. 2018 Jan 29;38(4):
pubmed: 29203639
Blood. 2006 Jun 15;107(12):4790-7
pubmed: 16514065
J Proteome Res. 2014 Aug 1;13(8):3679-84
pubmed: 24909410
Biochemistry. 2009 Mar 24;48(11):2538-49
pubmed: 19182904
Mol Cell. 2021 Sep 2;81(17):3468-3480.e7
pubmed: 34314700
Mol Immunol. 2008 Jan;45(1):13-24
pubmed: 17606294
Science. 2015 Apr 10;348(6231):1250834
pubmed: 25859050
Nature. 2011 May 19;473(7347):337-42
pubmed: 21593866
Cell Rep. 2014 Sep 25;8(6):1832-1844
pubmed: 25220455
Nature. 2021 Nov;599(7885):491-496
pubmed: 34711951
J Immunol. 2011 Sep 1;187(5):2696-701
pubmed: 21784977
Stat Appl Genet Mol Biol. 2004;3:Article3
pubmed: 16646809
Nat Chem Biol. 2021 Oct;17(10):1084-1092
pubmed: 34294896
Cell Discov. 2016 Nov 08;2:16040
pubmed: 27867533
J Biol Chem. 2014 Oct 17;289(42):28942-55
pubmed: 25147182
Biochem Soc Trans. 2016 Oct 15;44(5):1321-1337
pubmed: 27911715
Science. 2016 Apr 22;352(6284):453-9
pubmed: 27102483
EMBO J. 2020 Jul 1;39(13):e103695
pubmed: 32400009