Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis.
B7-1 Antigen
/ metabolism
CTLA-4 Antigen
/ metabolism
DNA-Binding Proteins
/ deficiency
Gene Knockout Techniques
Guanine Nucleotide Exchange Factors
/ deficiency
Homeostasis
Humans
Jurkat Cells
Primary Immunodeficiency Diseases
/ genetics
T-Lymphocytes
/ metabolism
rab GTP-Binding Proteins
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
15 07 2019
15 07 2019
Historique:
received:
31
08
2018
accepted:
29
05
2019
entrez:
17
7
2019
pubmed:
17
7
2019
medline:
19
12
2019
Statut:
epublish
Résumé
Immune responses need to be controlled tightly to prevent autoimmune diseases, yet underlying molecular mechanisms remain partially understood. Here, we identify biallelic mutations in three patients from two unrelated families in differentially expressed in FDCP6 homolog (DEF6) as the molecular cause of an inborn error of immunity with systemic autoimmunity. Patient T cells exhibit impaired regulation of CTLA-4 surface trafficking associated with reduced functional CTLA-4 availability, which is replicated in DEF6-knockout Jurkat cells. Mechanistically, we identify the small GTPase RAB11 as an interactor of the guanine nucleotide exchange factor DEF6, and find disrupted binding of mutant DEF6 to RAB11 as well as reduced RAB11
Identifiants
pubmed: 31308374
doi: 10.1038/s41467-019-10812-x
pii: 10.1038/s41467-019-10812-x
pmc: PMC6629652
doi:
Substances chimiques
B7-1 Antigen
0
CTLA-4 Antigen
0
DEF6 protein, human
0
DNA-Binding Proteins
0
Guanine Nucleotide Exchange Factors
0
rab11 protein
EC 3.6.1.-
rab GTP-Binding Proteins
EC 3.6.5.2
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
3106Subventions
Organisme : Austrian Science Fund FWF
ID : P 29951
Pays : Austria
Organisme : NIAID NIH HHS
ID : P01 AI061093
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI125179
Pays : United States
Commentaires et corrections
Type : ErratumIn
Références
J Clin Immunol. 2017 Nov;37(8):790-800
pubmed: 28956255
Inflamm Bowel Dis. 2015 Jan;21(1):40-7
pubmed: 25479458
J Clin Invest. 2015 Jun;125(6):2228-33
pubmed: 25893595
Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9273-8
pubmed: 9256472
Int Arch Allergy Immunol. 2016;171(1):45-53
pubmed: 27820937
Am J Hum Genet. 2012 Jun 8;90(6):986-1001
pubmed: 22608502
J Biol Chem. 2012 Sep 7;287(37):31073-84
pubmed: 22829599
Clin Immunol. 2018 Mar;188:52-57
pubmed: 29330115
Immunol Cell Biol. 2017 Oct;95(9):775-788
pubmed: 28611475
Immunol Rev. 2005 Apr;204:102-15
pubmed: 15790353
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Nature. 2014 Nov 27;515(7528):577-81
pubmed: 25428507
Immunity. 2003 Mar;18(3):403-14
pubmed: 12648457
Immunity. 1995 Nov;3(5):541-7
pubmed: 7584144
Nature. 2007 Feb 22;445(7130):936-40
pubmed: 17237761
J Immunol. 2009 Dec 1;183(11):7259-67
pubmed: 19915062
Nucleic Acids Res. 2017 Jul 3;45(W1):W567-W572
pubmed: 28520890
Prog Nucleic Acid Res Mol Biol. 2002;71:391-444
pubmed: 12102558
J Biol Chem. 2009 May 1;284(18):11882-91
pubmed: 19251698
Nat Med. 2014 Dec;20(12):1410-1416
pubmed: 25329329
Gut. 2015 Dec;64(12):1889-97
pubmed: 25367873
J Gastroenterol Hepatol. 2012 Jul;27(7):1159-66
pubmed: 22414241
Nature. 2015 Oct 1;526(7571):82-90
pubmed: 26367797
Nat Rev Microbiol. 2014 Sep;12(9):624-34
pubmed: 25118884
Biol Open. 2014 Dec 19;4(1):86-94
pubmed: 25527643
Nat Immunol. 2016 Dec;17(12):1352-1360
pubmed: 27776107
J Immunol. 1999 Aug 15;163(4):1868-79
pubmed: 10438921
J Immunol. 2007 Sep 15;179(6):3831-40
pubmed: 17785820
J Biol Chem. 2012 Mar 16;287(12):9429-40
pubmed: 22262842
Nat Rev Immunol. 2014 Jul;14(7):447-62
pubmed: 24948366
Nat Genet. 2016 Mar;48(3):323-30
pubmed: 26808113
J Exp Med. 2014 Oct 20;211(11):2137-49
pubmed: 25311508
Science. 1995 Nov 10;270(5238):985-8
pubmed: 7481803
Nature. 2016 Aug 17;536(7616):285-91
pubmed: 27535533
J Biol Chem. 2003 Oct 31;278(44):43541-9
pubmed: 12923183
Nucleic Acids Res. 2014 Jan;42(Database issue):D1253-60
pubmed: 24225319
Immunol Cell Biol. 2017 Oct;95(9):789-802
pubmed: 28652580
Intractable Rare Dis Res. 2014 Feb;3(1):8-11
pubmed: 25343120
Curr Opin Immunol. 2010 Dec;22(6):753-60
pubmed: 20869862
J Allergy Clin Immunol. 2012 Aug;130(2):481-8.e2
pubmed: 22721650
Science. 2014 Sep 26;345(6204):1623-1627
pubmed: 25213377
J Allergy Clin Immunol. 2012 Dec;130(6):1428-32
pubmed: 22981790
Annu Rev Immunol. 2016 May 20;34:121-49
pubmed: 26735698
Hum Immunol. 2003 Apr;64(4):389-401
pubmed: 12651066
Science. 2015 Jul 24;349(6246):436-40
pubmed: 26206937
Blood. 2017 Mar 16;129(11):1458-1468
pubmed: 28159733
J Clin Invest. 2007 Aug;117(8):2164-75
pubmed: 17657315
Nat Genet. 2014 Mar;46(3):310-5
pubmed: 24487276
Bioinformatics. 2010 Aug 15;26(16):2069-70
pubmed: 20562413
J Cell Sci. 2015 Dec 1;128(23):4341-52
pubmed: 26483383
Nat Methods. 2010 Apr;7(4):248-9
pubmed: 20354512
Cytometry B Clin Cytom. 2010 Nov;78(6):372-81
pubmed: 20533385
J Clin Invest. 2006 Mar;116(3):703-14
pubmed: 16470246
Immunol Rev. 2009 Nov;232(1):319-33
pubmed: 19909373
J Microsc. 2006 Dec;224(Pt 3):213-32
pubmed: 17210054
J Immunol. 2013 Jan 1;190(1):174-83
pubmed: 23197258
Mol Vis. 2012;18:1858-64
pubmed: 22815639
J Immunol. 1997 Jul 1;159(1):144-51
pubmed: 9200449
Adv Immunol. 2014;124:95-136
pubmed: 25175774
Sci Rep. 2016 Nov 08;6:36568
pubmed: 27824136
Phys Rev A. 1996 Nov;54(5):3863-3869
pubmed: 9913933
Immunity. 2008 Dec 19;29(6):899-911
pubmed: 19062315
Trends Immunol. 2015 Feb;36(2):63-70
pubmed: 25582039
Trends Cell Biol. 2006 Oct;16(10):522-9
pubmed: 16949823
Science. 2011 Apr 29;332(6029):600-3
pubmed: 21474713
PLoS Comput Biol. 2013;9(7):e1003153
pubmed: 23874191
Nat Protoc. 2009;4(7):1073-81
pubmed: 19561590
Cytometry A. 2015 Jan;87(1):81-5
pubmed: 25132325