Splicing factor SRSF1 controls T cell hyperactivity and systemic autoimmunity

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)...

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Bibliographic Details
Published in:The Journal of clinical investigation 2019-12, Vol.129 (12), p.5411-5423
Main Authors: Katsuyama, Takayuki, Li, Hao, Comte, Denis, Tsokos, George C, Moulton, Vaishali R
Format: Article
Language:English
Subjects:
Autoimmunity
B cells
Biochemistry
Development and progression
Gene expression
Genes
Health aspects
Hyperactivity
Kidney diseases
Lupus
Lupus erythematosus
Nephritis
Physiological aspects
Protein binding
RNA
Systemic lupus erythematosus
T cells
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Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI127949