Abstract
Increasing evidence indicates that alternative processing of mRNA, including alternative splicing, 3' alternative polyadenylation, and regulation of mRNA stability/translation, represents a major mechanism contributing to protein diversification. For example, in alternative polyadenylation, the 3' end of the immunoglobulin heavy chain mRNA is processed during B cell differentiation, and this processing involves RNA-binding proteins. hnRNPLL (heterogeneous nuclear ribonucleoprotein L-like protein) is an RNA-binding protein expressed in terminally differentiated lymphocytes, such as memory T cells and plasma cells. hnRNPLL regulates various processes of RNA metabolism, including alternative pre-mRNA splicing and RNA stability. In plasma cells, hnRNPLL also regulates the transition from the membrane isoform of the immunoglobulin heavy-chain (mIgH) to the secreted isoform (sIgH), but the precise mechanism remains to be identified. In this study, we report that hnRNPLL specifically associates with cytoplasmic PABPC1 (poly(A)-binding protein 1) in both T cells and plasma cells. We found that although PABPC1 is not required for the alternative splicing of CD45, a primary target of hnRNPLL in lymphocytes, PABPC1 does promote the binding of hnRNPLL to the immunoglobulin mRNA and regulates switching from mIgH to sIgH in plasma cells. Given the recently identified role of PABPC1 in mRNA alternative polyadenylation, our findings suggest that PABPC1 recruits hnRNPLL to the 3'-end of RNA and regulates the transition from membrane Ig to secreted Ig through mRNA alternative polyadenylation. In conclusion, our study has revealed a mechanism that regulates immunoglobulin secretion in B cells via cooperation between a plasma cell-specific RBP (hnRNPLL) and a universally expressed RBP (PABPC1).
Highlights
Increasing evidence indicates that alternative processing of mRNA, including alternative splicing, 3 alternative polyadenylation, and regulation of mRNA stability/translation, represents a major mechanism contributing to protein diversification
Given the predominant 3Ј-UTR binding of hnRNPLL identified in previous PAR-CLIP experiments [17], we postulated that hnRNPLL and PABPC1 might cooperate to regulate certain aspects of the mRNA 3Ј-end processing
We identified PABPC1 as a protein that interacts with hnRNPLL to regulating mIg to sIg switching in plasma cells
Summary
Increasing evidence indicates that alternative processing of mRNA, including alternative splicing, 3 alternative polyadenylation, and regulation of mRNA stability/translation, represents a major mechanism contributing to protein diversification. Our study has revealed a mechanism that regulates immunoglobulin secretion in B cells via cooperation between a plasma cell-specific RBP (hnRNPLL) and a universally expressed RBP (PABPC1). Various RNA-binding proteins (RBPs) have been identified as regulating the cell-type-specific selection of secreted IgH versus membrane-bound IgH. These RBPs mainly include polyadenylation/cleavage factors (i.e. CstF64) [8], splicing factors [9, 10], and elongation factors [10, 11]. Our study revealed a mechanism regulating immunoglobulin secretion in B cells through cooperation between a plasma cell-specific RBP (hnRNPLL) and a universally expressed RBP (PABPC1)
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