Consequences of Increased CD45RA and RC Isoforms for TCR Signaling and Peripheral T Cell Deficiency Resulting from Heterogeneous Nuclear Ribonucleoprotein L-Like Mutation

Wu, Zuopeng; Yates, Adele; Hoyne, Gerard F.; Goodnow, Christopher C.

doi:10.4049/jimmunol.0903625

Cited by 27 publications

(32 citation statements)

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“…It is apparent that the influence of hnRNPLL on T-cell function goes beyond its ability to facilitate exon exclusion in CD45 pre-mRNA transcripts (12,20), as indicated by the effect on processing of diverse target mRNAs in activated T cells (12,20), and because breeding a mouse strain harboring a hnRNPLL V136D mutation onto a CD45-deficient background did not mitigate the functional impact of the hnRNPLL V136D mutation on in vivo T-cell survival and homeostasis (21). In plasma cells as in T cells (12), hnRNPLL regulates the alternative splicing of CD44 premRNA, indicating an overlap of targets between these two cell types.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneous nuclear ribonucleoprotein L-like (hnRNPLL) and elongation factor, RNA polymerase II, 2 (ELL2) are regulators of mRNA processing in plasma cells

Benson

Äijö

Chang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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B cells and plasma cells possess distinct RNA processing environments that respectively promote the expression of membrane-associated Ig by B cells versus the secretion of Ig by plasma cells. Through a combination of transcriptional profiling and screening using a lentiviral short-hairpin RNA interference library, we show that both the splicing factor hnRNPLL and the transcription elongation factor ELL2 modulate the ratio of secreted versus membrane-encoding Ighg2b transcripts in MPC11 plasmacytoma cell lines. hnRNPLL and ELL2 are both highly expressed in primary plasma cells relative to B cells, but hnRNPLL binds Ighg2b mRNA transcripts and promotes an increase in levels of the membrane-encoding Ighg2b isoform at the expense of the secreted Ighg2b isoform, whereas ELL2 counteracts this effect and drives Ig secretion by increasing the frequency of the secreted Ighg2b isoform. As in T cells, hnRNPLL also alters the splicing pattern of mRNA encoding the adhesion receptor CD44, promoting exon inclusion, and decreasing the overall level of CD44 expression. Further characterization of ELL2-dependent transcription by RNA-Seq revealed that ∼12% of transcripts expressed by plasma cells were differentially processed because of the activities of ELL2, including B-cell maturation antigen BCMA, a receptor with a defined role in plasma cell survival. Taken together, our data identify hnRNPLL and ELL2 as regulators of pre-mRNA processing in plasma cells.ne of the earliest examples of a single gene encoding multiple transcripts and protein species was provided by genes encoding the Ig heavy chain (IgH) (1-3). The discovery that the IgH genes are alternatively processed at their 3′ ends explained how they could generate transcripts encoding both membrane-associated and secreted Ig, with B cells primarily expressing the former and plasma cells the latter. The levels of membrane-encoding and secreted IgH transcripts are controlled by the mutually exclusive use of a splice site versus a cleavage/polyadenylation [poly(A)] site at the 3′ end of the IgH pre-mRNA transcript (see diagram in Fig. 1A). In IgG-expressing B cells, the C H 3 exon (or, in IgM-expressing B cells, the C H 4 exon) is spliced to downstream M1 and M2 exons encoding the transmembrane and cytoplasmic domains of membrane Ig (mIg), respectively, with the membrane-associated poly(A) [mbp(A)] site used. In plasma cells, a weak poly(A) sequence [secp (A)] located downstream to the C H 3 exon is included in the final mRNA transcript, with recognition of the secp(A) producing a truncated transcript encoding secreted Ig (sIg) (4, 5). B cells express nearly equivalent levels of sIgH and mIgH transcripts; upon antigen-driven activation and differentiation into plasma cells, sIgH transcripts are overwhelmingly increased in frequency (5, 6). Overall, therefore, the B-cell mRNA processing environment is tilted toward enhanced mRNA splicing at the expense of the cleavage/polyadenylation reaction (7-9). In contrast, the plasma cell mRNA processing environment is tilted toward en...

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Section: Discussionmentioning

confidence: 99%

Heterogeneous nuclear ribonucleoprotein L-like (hnRNPLL) and elongation factor, RNA polymerase II, 2 (ELL2) are regulators of mRNA processing in plasma cells

Benson

Äijö

Chang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…The lifespan of Hrnpll thu homozygous T cells is greatly shortened, resulting in decreased numbers of naïve T cells in the circulation [16] due to effects on hnRNPLL targets other than Ptprc [22]. We focused on Senp2 as an additional candidate, since it was highly ranked and validated with strong evidence of intron inclusion and cryptic splicing that would decrease the pool of normal Senp2 protein in the analysis of Hrnpll thu homozygous OT-1 T cells above, and because it is an essential regulator of protein sumoylation with the capacity to affect many aspects of cell survival in non-lymphoid cells [31,32].…”

Section: Resultsmentioning

confidence: 99%

“…This effect of hnRNPLL deficiency occurs even in T cells with a null Ptprc gene [22], indicating that hnRNPLL controls other genes contributing to T cell persistence that have yet to be identified. Here we use this mammalian system to analyze the consequences of perturbing hnRNPLL either by mutation or natural expression differences, as revealed by global mRNA changes measured by RNA-seq.…”

Section: Introductionmentioning

confidence: 99%

The RNA-binding protein hnRNPLL induces a T cell alternative splicing program delineated by differential intron retention in polyadenylated RNA

et al. 2014

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BackgroundRetention of a subset of introns in spliced polyadenylated mRNA is emerging as a frequent, unexplained finding from RNA deep sequencing in mammalian cells.ResultsHere we analyze intron retention in T lymphocytes by deep sequencing polyadenylated RNA. We show a developmentally regulated RNA-binding protein, hnRNPLL, induces retention of specific introns by sequencing RNA from T cells with an inactivating Hnrpll mutation and from B lymphocytes that physiologically downregulate Hnrpll during their differentiation. In Ptprc mRNA encoding the tyrosine phosphatase CD45, hnRNPLL induces selective retention of introns flanking exons 4 to 6; these correspond to the cassette exons containing hnRNPLL binding sites that are skipped in cells with normal, but not mutant or low, hnRNPLL. We identify similar patterns of hnRNPLL-induced differential intron retention flanking alternative exons in 14 other genes, representing novel elements of the hnRNPLL-induced splicing program in T cells. Retroviral expression of a normally spliced cDNA for one of these targets, Senp2, partially corrects the survival defect of Hnrpll-mutant T cells. We find that integrating a number of computational methods to detect genes with differentially retained introns provides a strategy to enrich for alternatively spliced exons in mammalian RNA-seq data, when complemented by RNA-seq analysis of purified cells with experimentally perturbed RNA-binding proteins.ConclusionsOur findings demonstrate that intron retention in mRNA is induced by specific RNA-binding proteins and suggest a biological significance for this process in marking exons that are poised for alternative splicing.

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“…More importantly, breeding the Thunder mouse strain onto a CD45-deficient background did not mitigate the impact of the hnRNPLL mutation on in vivo T-cell survival and homeostasis. 44 It will remain to be determined what downstream targets of hnRNPLL are important in regulating T-cell homeostasis. Overexpression of a spliced form of Senp2 gene in Thunder mutant CD8 T cells partially reversed the survival defects in vivo, suggesting that aberrant splicing of Senp2 may contribute to the T-cell survival defects.…”

Section: Immunoglobulinmentioning

confidence: 99%

“…However, experimental evidence fails to support this hypothesis. 44 First, although thunder T cells have elevated expression of CD45RA and CD45RC, the mutation has little effect on Lck phosphorylation downstream of CD45, T-cell activation, or thymic T-cell selection. More importantly, breeding the Thunder mouse strain onto a CD45-deficient background did not mitigate the impact of the hnRNPLL mutation on in vivo T-cell survival and homeostasis.…”

Section: Immunoglobulinmentioning

confidence: 99%

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

Chang

2016

WIREs RNA

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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 For further resources related to this article, please visit the WIREs website.

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Consequences of Increased CD45RA and RC Isoforms for TCR Signaling and Peripheral T Cell Deficiency Resulting from Heterogeneous Nuclear Ribonucleoprotein L-Like Mutation

Abstract: Material Supplementary 5.DC1http://www.jimmunol.org/content/suppl/2010/05/26/jimmunol.090362

Cited by 27 publications

References 44 publications

Heterogeneous nuclear ribonucleoprotein L-like (hnRNPLL) and elongation factor, RNA polymerase II, 2 (ELL2) are regulators of mRNA processing in plasma cells

Heterogeneous nuclear ribonucleoprotein L-like (hnRNPLL) and elongation factor, RNA polymerase II, 2 (ELL2) are regulators of mRNA processing in plasma cells

The RNA-binding protein hnRNPLL induces a T cell alternative splicing program delineated by differential intron retention in polyadenylated RNA

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

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