Act1 is a negative regulator in T and B cells via direct inhibition of STAT3.

Nature Communications
Cun-Jin ZhangXiaoxia Li

Abstract

Although Act1 (adaptor for IL-17 receptors) is necessary for IL-17-mediated inflammatory responses, Act1- (but not Il17ra-, Il17rc-, or Il17rb-) deficient mice develop spontaneous SLE- and Sjögren's-like diseases. Here, we show that Act1 functions as a negative regulator in T and B cells via direct inhibition of STAT3. Mass spectrometry analysis detected an Act1-STAT3 complex, deficiency of Act1 (but not Il17ra-, Il17rc-, or Il17rb) results in hyper IL-23- and IL-21-induced STAT3 activation in T and B cells, respectively. IL-23R deletion or blockade of IL-21 ameliorates SLE- and Sjögren's-like diseases in Act1-/- mice. Act1 deficiency results in hyperactivated follicular Th17 cells with elevated IL-21 expression, which promotes T-B cell interaction for B cell expansion and antibody production. Moreover, anti-IL-21 ameliorates the SLE- and Sjögren's-like diseases in Act1-deficient mice. Thus, IL-21 blocking antibody might be an effective therapy for treating SLE- and Sjögren's-like syndrome in patients containing Act1 mutation.

References

Aug 30, 2000·Proceedings of the National Academy of Sciences of the United States of America·X LiG R Stark
Mar 7, 2007·The Journal of Immunology : Official Journal of the American Association of Immunologists·Deborah HerberKyri Dunussi-Joannopoulos
Jan 10, 2009·Annual Review of Immunology·Thomas KornVijay K Kuchroo
Jan 22, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Estefania ClaudioUlrich Siebenlist
Jan 22, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Shadi SwaidaniXiaoxia Li
Jan 24, 2009·Proceedings of the National Academy of Sciences of the United States of America·Jason A BubierDerry C Roopenian
May 13, 2009·Nature Reviews. Rheumatology·Francesco AnnunziatoSergio Romagnani
Aug 1, 2009·Arthritis and Rheumatism·Ryan WebbAmr H Sawalha
Nov 26, 2009·International Immunology·Rosanne Spolski, Warren J Leonard
May 12, 2010·Nature Reviews. Rheumatology·George K Bertsias, Dimitrios T Boumpas
Jun 29, 2010·European Journal of Immunology·Akihiro Kimura, Tadamitsu Kishimoto
Jul 28, 2010·Proceedings of the National Academy of Sciences of the United States of America·Meike MitsdoerfferVijay K Kuchroo
Oct 19, 2010·Nature Genetics·Eva EllinghausAndre Franke
Oct 19, 2010·Nature Genetics·UNKNOWN Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2Richard C Trembath
Apr 16, 2011·Trends in Immunology·Jarod ZeppXiaoxia Li
Nov 3, 2011·Immunology·Elissa K Deenick, Cindy S Ma
Dec 2, 2011·The New England Journal of Medicine·George C Tsokos
Mar 1, 2012·Nihon Rinshō Men'eki Gakkai kaishi = Japanese journal of clinical immunology·Yasuko NakagawaTakao Koike
May 16, 2012·European Journal of Immunology·Angela C JohnsonTrine N Jørgensen
Jul 4, 2012·The Journal of Experimental Medicine·Cindy S MaStuart G Tangye
Oct 2, 2012·Nature Reviews. Drug Discovery·Pierre Miossec, Jay K Kolls
Sep 3, 2013·Nature Neuroscience·Zizhen KangXiaoxia Li
Jul 16, 2014·The Journal of Immunology : Official Journal of the American Association of Immunologists·Ling WuXiaoxia Li
Aug 26, 2014·Nature Reviews. Immunology·Sarah L GaffenDaniel J Cua
Aug 21, 2016·The Journal of Immunology : Official Journal of the American Association of Immunologists·Cun-Jin ZhangYaping Yan
Feb 22, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jin-Young ChoiJoe Craft
Jun 5, 2017·Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology·Yongxiang YangZhuyi Li

❮ Previous
Next ❯

Citations

Jan 26, 2020·Nutrients·Erin A YamamotoTrine N Jørgensen
Mar 1, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Zhuo LiuCun-Jin Zhang
Mar 25, 2020·Thyroid : Official Journal of the American Thyroid Association·Yongping LiuWeiping Teng
Jun 6, 2019·Arthritis Research & Therapy·Ji-Won KimSung-Hwan Park
Jan 3, 2020·Omics : a Journal of Integrative Biology·Ege ErtekinKutlu O Ulgen
Nov 15, 2020·Biomolecules·William de Jesús Ríos-RíosHonorio Torres-Aguilar
Feb 7, 2021·The Journal of Investigative Dermatology·Alex LipovskyEric R Goedken
Apr 6, 2021·Journal of Immunology Research·Kailei Guo, Xiaomin Zhang

❮ Previous
Next ❯

Methods Mentioned

BETA
co-immunoprecipitation
proximity ligation assay
immunoprecipitation
flow cytometry
ELISA
genotyping
PCR
transfection
proximity
Fluorescence

Related Concepts

Related Feeds