Abstract
Angulin proteins are a group of evolutionally conserved type I transmembrane proteins that contain an extracellular Ig-like domain. In mammals, three angulin proteins have been identified, namely immunoglobulin-like domain containing receptor 1 (ILDR1), immunoglobulin-like domain containing receptor 2 (ILDR2), and lipolysis-stimulated lipoprotein receptor (LSR). All three proteins have been shown to localize at tight junctions (TJs) and are important for TJ formation. Mutations in ILDR1 gene have been shown to cause non-syndromic hearing loss (NSHL). In the present work, we show that ILDR1 binds to splicing factors TRA2A, TRA2B, and SRSF1, and translocates into the nuclei when the splicing factors are present. Moreover, ILDR1 affects alternative splicing of Tubulin delta 1 (TUBD1), IQ motif containing B1 (IQCB1), and Protocadherin 19 (Pcdh19). Further investigation show that ILDR2, but not LSR, also binds to the splicing factors and regulates alternative splicing. When endogenous ILDR1 and ILDR2 expression is knockdown with siRNAs in cultured cells, alternative splicing of TUBD1 and IQCB1 is affected. In conclusion, we show here that angulin proteins ILDR1 and ILDR2 are involved in alternative pre-mRNA splicing via binding to splicing factors TRA2A, TRA2B, or SRSF1.
Highlights
Immunoglobulin-like domain containing receptor 1 (ILDR1) is a putative type I transmembrane protein containing an immunoglobulin (Ig)-like extracellular N-terminal domain[1]
Another SR protein, SRSF5, was included in the experiment, and the results showed that SRSF5 is not co-immunoprecipitated with immunoglobulin-like domain containing receptor 1 (ILDR1), confirming the specific interaction between ILDR1 and Transformer 2 protein homolog alpha (TRA2A)/transformer 2 protein homolog beta (TRA2B)/serine/ arginine-rich splicing factor 1 (SRSF1) (Fig. 1C)
All three angulin proteins have been shown to localize at tight junctions (TJs) and could recruit tricellulin, another important TJ component[2, 30]
Summary
Immunoglobulin-like domain containing receptor 1 (ILDR1) is a putative type I transmembrane protein containing an immunoglobulin (Ig)-like extracellular N-terminal domain[1]. Ildr[1] mRNA was detected in hair cells as well as supporting cells, and ILDR1 protein was shown to localize at tricellular tight junctions (tTJs)[2, 3] Another tight junction protein, tricellulin, is required for the structure and function of tTJs, and mutations of tricellulin gene cause autosomal recessive hearing impairment DFNB497. ILDR1 is suggested to play an important role in regulating the integration of tTJs, it seems that this protein is involved in functions other than tTJs in the inner ear Consistent with this hypothesis, hair cell degeneration in Ildr[1] knockout mice is more severe than that in tricellulin mutant mice[4, 8]. We show that ILDR1 as well as its paralog ILDR2 could regulate alternative pre-mRNA splicing via binding to TRA2A, TRA2B, and SRSF1
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