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RNA‐binding protein hnRNPLL as a critical regulator of lymphocyte homeostasis and differentiation

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RNA‐binding proteins orchestrate posttranscriptional regulation of gene expression, such as messenger RNA (mRNA) splicing, RNA stability regulation, and translation regulation. Heterogeneous nuclear RNA‐binding proteins (hnRNPs) refer to a collection of unrelated RNA‐binding proteins predominantly located in the nucleus (Han et al. Biochem J 2010, 430:379–392). Although canonical functions of hnRNPs are to promote pre‐mRNA splicing, they are involved in all the processes of RNA metabolism through recognizing specific cis‐elements on RNA (Dreyfuss et al. Annu Rev Biochem 1993, 62:289–321; Huelga et al. Cell Rep 2012, 1:167–178; Krecic and Swanson. Curr Opin Cell Biol 1999, 11:363–371). Heterogeneous nuclear RNA‐binding protein L like (hnRNPLL) is a tissue‐specific hnRNP, which was identified as a regulator of CD45RA to CD45RO switching during memory T‐cell development (Oberdoerffer et al. Science 2008, 321:686–691; Topp et al. RNA 2008, 14:2038–2049; Wu et al. Immunity 2008, 29:863–875). Since then, hnRNPLL has emerged as a critical regulator of lymphocyte homeostasis and terminal differentiation, controlling alternative splicing or expression of critical genes for the lymphocytes development (Wu et al. Immunity 2008, 29:863–875; Chang et al. Proc Natl Acad Sci USA 2015, 112:E1888–E1897). This review will summarize recent advances in understanding the functions of hnRNPLL, focusing on its biochemical functions and physiological roles in lymphocyte differentiation and homeostasis. WIREs RNA 2016, 7:295–302. doi: 10.1002/wrna.1335 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Development
Heterogeneous nuclear RNA‐binding protein L like (hnRNPLL) regulates splicing of CD45. (a) Alternative splicing of CD45. Naïve primary T cells express the larger isoforms of CD45 and are RA+ or RB+; immature and mature B cells express the largest isoform CD45RABC (commonly known as B220). Activated/memory T cells and plasma cells express the shortest isoform (RO). (Reprinted with permission from Ref . Copyright 2004 Macmillan Publishers Ltd: Nature). (b) hnRNPLL mediates activation‐induced splice‐out of exon A and exon C. The splicing of exon B, however, is dependent on the DNA methylation and CTCF binding to this exon.
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A proposed model of heterogeneous nuclear RNA‐binding protein L like (hnRNPLL) in regulating plasma‐cell differentiation. hnRNPLL expression is induced in plasma cells, which recognizes CA repeat element on pre‐messenger RNA (mRNA). hnRNPLL can either regulate alternative splicing of genes essential for plasma cells (e.g., IRF4, Oct1) or promote mRNA stability. Although hnRNPLL is not required for initial acquisition of plasma cell markers, it is indispensable for full commitment to plasma cell lineage, including quiescence and maximal immunoglobulin production.
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RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA in Disease and Development > RNA in Development

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