Splicing factor SRSF1 acts as a novel molecular brake for CD4 T cell activation and controls key molecular pathways in SLE

Rhea Bhargava^1,2,3*, Michelle Lee^1,3, Rohit Upadhyay², Vaishali R. Moulton¹

¹Department of Medicine, Division of Rheumatology and Clinical Immunology,

Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA

²John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA

³Equal contribution co-first authors

*Corresponding author: Dr. Rhea Bhargava Email: rbhargav@bidmc.harvard.edu

Keywords: SRSF1, SLE, CD4 T cells, transcriptomics, Comparative bioinformatics

Significance statement: In this study, we identified 169 overlapping genes controlled by SRSF1, which were aberrantly expressed in patients with SLE. Pathway analysis unveiled that these genes were enriched in interferon signaling, cytokine production, cytokine receptor interaction, cell migration, and lysosomal clearance pathways. The findings also showed that SRSF1 plays a crucial role in regulating genes involved in T cell homeostasis, activation, cytokine regulation/signaling, and differentiation, all of which were found to be altered in patients with SLE. Moreover, the study suggested that SRSF1 plays an important role in regulating T cell function and its deficiency may lead to a hyperactive T cell phenotype in patients with SLE. These findings shed light on the potential mechanisms underlying the development of SLE and highlight potential of SRSF1 as a therapeutic target for treating SLE.