Splicing factor SRSF1 controls T cell hyperactivity and systemic autoimmunity.

Détails

ID Serval
serval:BIB_F5E40706ED4B
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Splicing factor SRSF1 controls T cell hyperactivity and systemic autoimmunity.
Périodique
The Journal of clinical investigation
Auteur⸱e⸱s
Katsuyama T., Li H., Comte D., Tsokos G.C., Moulton V.R.
ISSN
1558-8238 (Electronic)
ISSN-L
0021-9738
Statut éditorial
Publié
Date de publication
02/12/2019
Peer-reviewed
Oui
Volume
129
Numéro
12
Pages
5411-5423
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
Systemic lupus erythematosus (SLE) is a devastating autoimmune disease in which hyperactive T cells play a critical role. Understanding molecular mechanisms underlying the T cell hyperactivity will lead to identification of specific therapeutic targets. Serine/arginine-rich splicing factor 1 (SRSF1) is an essential RNA-binding protein that controls posttranscriptional gene expression. We have demonstrated that SRSF1 levels are aberrantly decreased in T cells from patients with SLE and that they correlate with severe disease, yet the role of SRSF1 in T cell physiology and autoimmune disease is largely unknown. Here we show that T cell-restricted Srsf1-deficient mice develop systemic autoimmunity and lupus-nephritis. Mice exhibit increased frequencies of activated/effector T cells producing proinflammatory cytokines, and an elevated T cell activation gene signature. Mechanistically, we noted increased activity of the mechanistic target of rapamycin (mTOR) pathway and reduced expression of its repressor PTEN. The mTOR complex 1 (mTORC1) inhibitor rapamycin suppressed proinflammatory cytokine production by T cells and alleviated autoimmunity in Srsf1-deficient mice. Of direct clinical relevance, PTEN levels correlated with SRSF1 in T cells from patients with SLE, and SRSF1 overexpression rescued PTEN and suppressed mTORC1 activation and proinflammatory cytokine production. Our studies reveal the role of a previously unrecognized molecule, SRSF1, in restraining T cell activation, averting the development of autoimmune disease, and acting as a potential therapeutic target for lupus.
Mots-clé
Animals, Autoimmunity, Cytokines/biosynthesis, Humans, Lupus Nephritis/etiology, Lymphocyte Activation, Mechanistic Target of Rapamycin Complex 1/physiology, Mice, Mice, Inbred C57BL, PTEN Phosphohydrolase/analysis, PTEN Phosphohydrolase/genetics, Serine-Arginine Splicing Factors/physiology, Signal Transduction, Sirolimus/pharmacology, T-Lymphocytes/immunology, TOR Serine-Threonine Kinases/physiology, Cytokines, Immunology, Lupus, T cells
Pubmed
Web of science
Open Access
Oui
Création de la notice
04/01/2020 12:40
Dernière modification de la notice
19/12/2020 7:26
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