Alternative Splicing: A New Cause and Potential Therapeutic Target in Autoimmune Disease

Abstract

Alternative splicing (AS) is a complex coordinated transcriptional regulatory mechanism. It affects nearly 95% of all protein-coding genes and occurs in nearly all human organs. Aberrant alternative splicing can lead to various neurological diseases and cancers and is responsible for aging, infection, inflammation, immune and metabolic disorders, and so on. Though aberrant alternative splicing events and their regulatory mechanisms are widely recognized, the association between autoimmune disease and alternative splicing has not been extensively examined. Autoimmune diseases are characterized by the loss of tolerance of the immune system towards self-antigens and organ-specific or systemic inflammation and subsequent tissue damage. In the present review, we summarized the most recent reports on splicing events that occur in the immunopathogenesis of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and attempted to clarify the role that splicing events play in regulating autoimmune disease progression. We also identified the changes that occur in splicing factor expression. The foregoing information might improve our understanding of autoimmune diseases and help develop new diagnostic and therapeutic tools for them.

Transcription and splicing regulation by NLRC5 shape the interferon response in human pancreatic β cells

“…Among the identified RBPs that are regulated by IFNα via NLRC5 are NOVA1 , NOVA2 , and RBFOX1 , previously shown by us to modulate β cell viability and function ( 44 , 45 ). Splicing alterations might contribute to pancreatic β cell demise and its recognition by the immune system in the context of T1D ( 29 , 50 , 62 ) and other autoimmune diseases ( 6 , 63 ) and may also have an impact on the role for candidate genes in T1D and other diseases ( 29 , 64 , 65 ). Alternative splicing plays also a regulatory role for β cell identity, development, function, and survival ( 29 , 44 , 64 , 66 – 69 ).…”

Alternative RNA splicing in cancer: what about adult T-cell leukemia?

“…SFs such as SR (serine/arginine-rich) proteins and hnRNPs (heterogeneous nuclear ribonucleoproteins) are RNA-binding proteins and are considered as enhancers ( 50 , 51 ) and silencers ( 52 , 53 ) respectively since SR proteins are typically recruited to ISEs and ESEs (respectively intronic & exonic splicing enhancers) while hnRNPs usually bind to ISSs and ESSs ( Figure 3B ). Disruptions of the splicing mechanism and regulation have been documented in many pathologies, ranging from genetic ( 54 – 56 ) and autoimmune ( 57 , 58 ) diseases, to cancers; the latter being the center of discussion in the following sections.…”

New insights into pathogen-mediated modulation of host RNA splicing

“…Furthermore, it had been known that many plant key regulators, such as immune receptors, phytochrome receptors and transcription factors, are subjected to AS (Rigo et al, 2019). And, the aberrant AS patterns are frequently associated with development and immune dysfunction (Ren et al, 2021).…”