Regulation of CTLA-4 recycling by LRBA and Rab11.
CTLA-4
LRBA
Rab GTPase
Rab11
T cells
recycling
trafficking
Journal
Immunology
ISSN: 1365-2567
Titre abrégé: Immunology
Pays: England
ID NLM: 0374672
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
revised:
30
03
2021
received:
01
03
2021
accepted:
13
04
2021
pubmed:
8
5
2021
medline:
6
10
2021
entrez:
7
5
2021
Statut:
ppublish
Résumé
CTLA-4 is an essential regulator of T-cell immune responses whose intracellular trafficking is a hallmark of its expression. Defects in CTLA-4 trafficking due to LRBA deficiency cause profound autoimmunity in humans. CTLA-4 rapidly internalizes via a clathrin-dependent pathway followed by poorly characterized recycling and degradation fates. Here, we explore the impact of manipulating Rab GTPases and LRBA on CTLA-4 expression to determine how these proteins affect CTLA-4 trafficking. We observe that CTLA-4 is distributed across several compartments marked by Rab5, Rab7 and Rab11 in both HeLa and Jurkat cells. Dominant negative (DN) inhibition of Rab5 resulted in increased surface CTLA-4 expression and reduced internalization and degradation. We also observed that constitutively active (CA) Rab11 increased, whereas DN Rab11 decreased CTLA-4 surface expression via an impact on CTLA-4 recycling, indicating CTLA-4 shares similarities with other recycling receptors such as EGFR. Additionally, we studied the impact of manipulating both LRBA and Rab11 on CTLA-4 trafficking. In Jurkat cells, LRBA deficiency was associated with markedly impaired CTLA-4 recycling and increased degradation that could not be corrected by expressing CA Rab11. Moreover LRBA deficiency reduced CTLA-4 colocalization with Rab11, suggesting that LRBA is upstream of Rab11. These results show that LRBA is required for effective CTLA-4 recycling by delivering CTLA-4 to Rab11 recycling compartments, and in its absence, CTLA-4 fails to recycle and undergoes degradation.
Identifiants
pubmed: 33960403
doi: 10.1111/imm.13343
pmc: PMC8358724
mid: EMS126082
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
CTLA-4 Antigen
0
Clathrin
0
LRBA protein, human
EC 2.7.10.-
rab11 protein
EC 3.6.1.-
rab GTP-Binding Proteins
EC 3.6.5.2
rab5 GTP-Binding Proteins
EC 3.6.5.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
106-119Subventions
Organisme : Wellcome Trust Clinical PhD Studentship
ID : 110297/Z/15/Z
Organisme : Wellcome Trust
ID : 204798
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/H013598/2
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 20478/Z/16
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/M503290/1
Pays : United Kingdom
Organisme : Versus Arthritis
ID : 21147
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/M009203/1
Pays : United Kingdom
Informations de copyright
© 2021 The Authors. Immunology published by John Wiley & Sons Ltd.
Références
Immunity. 2002 Jan;16(1):23-35
pubmed: 11825563
Immunity. 1995 Nov;3(5):541-7
pubmed: 7584144
Cell. 1991 Mar 8;64(5):915-25
pubmed: 1900457
Nature. 2001 Mar 29;410(6828):608-11
pubmed: 11279502
Cell. 1992 Sep 4;70(5):729-40
pubmed: 1516131
J Biol Chem. 2012 Mar 16;287(12):9429-40
pubmed: 22262842
J Biol Chem. 2011 Oct 7;286(40):35196-208
pubmed: 21832070
Immunol Cell Biol. 2017 Oct;95(9):789-802
pubmed: 28652580
Nature. 2001 Mar 29;410(6828):604-8
pubmed: 11279501
Am J Hum Genet. 2012 Jun 8;90(6):986-1001
pubmed: 22608502
Nat Rev Mol Cell Biol. 2009 Aug;10(8):513-25
pubmed: 19603039
Cell. 1992 Sep 4;70(5):715-28
pubmed: 1516130
Science. 2015 Apr 3;348(6230):56-61
pubmed: 25838373
Nat Med. 2014 Dec;20(12):1410-1416
pubmed: 25329329
Mol Cell Biol. 2014 Apr;34(8):1486-99
pubmed: 24515439
J Cell Biol. 1994 May;125(3):573-82
pubmed: 7909812
PLoS One. 2013;8(4):e60903
pubmed: 23565286
Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9273-8
pubmed: 9256472
J Allergy Clin Immunol. 2007 Oct;120(4):744-50; quiz 751-2
pubmed: 17931557
J Autoimmun. 2013 Sep;45:49-57
pubmed: 23849743
J Immunol. 1999 Aug 15;163(4):1868-79
pubmed: 10438921
J Biol Chem. 1995 Oct 20;270(42):25107-14
pubmed: 7559643
Science. 1995 Nov 10;270(5238):985-8
pubmed: 7481803
J Cell Biol. 2000 May 15;149(4):901-14
pubmed: 10811830
Science. 2008 Oct 10;322(5899):271-5
pubmed: 18845758
Cell. 2005 Sep 9;122(5):735-49
pubmed: 16143105
Immunity. 2002 Aug;17(2):201-10
pubmed: 12196291
Science. 2014 Sep 26;345(6204):1623-1627
pubmed: 25213377
Science. 2015 Jul 24;349(6246):436-40
pubmed: 26206937
Blood. 2017 Mar 16;129(11):1458-1468
pubmed: 28159733
J Biol Chem. 2006 Jan 13;281(2):1099-106
pubmed: 16282324
Immunity. 1997 May;6(5):583-9
pubmed: 9175836
Immunol Cell Biol. 2017 Oct;95(9):775-788
pubmed: 28611475
EMBO J. 1993 Feb;12(2):677-82
pubmed: 8440258
J Immunol. 1997 Jul 1;159(1):144-51
pubmed: 9200449
J Cell Biol. 1996 Nov;135(4):913-24
pubmed: 8922376
Mol Biol Cell. 2000 Feb;11(2):467-80
pubmed: 10679007
Science. 2011 Apr 29;332(6029):600-3
pubmed: 21474713
J Immunol. 2005 Apr 15;174(8):4803-11
pubmed: 15814706