Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 46, Issue 6, Pages 1490-1503Publisher
WILEY
DOI: 10.1002/eji.201545663
Keywords
CD5; Alternative polyadenylation; PTB/PTBP1; miR-204; T-lymphocyte activation
Categories
Funding
- FEDER - Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 - Operacional Programme for Competitiveness and Internationalisation (POCI) Portugal 2020
- Portuguese funds through FCT - Fundacao para a Ciencia e a Tecnologia/Ministerio da Ciencia, Tecnologia e Inovacao in the framework of the project Institute for Research and Innovation in Health Sciences [POCI-01-0145-FEDER-007274]
- Operational Competitiveness Programme - COMPETE [FCOMP-01-0124-FEDER-037277 (PEst-C/SAU/LA0002/2013), FCOMP-01-0124-FEDER-021201 (PTDC/SAU-GMG/116621/2010), FCOMP-01-0124-FEDER-028252 (PTDC/BEX-BCM/0468/2012)]
- FCT [SFRH/BPD/107901/2015]
- American-Portuguese Biomedical Research Fund
- Nancy Chang Award for Research Excellence
- Fundação para a Ciência e a Tecnologia [SFRH/BPD/107901/2015] Funding Source: FCT
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T lymphocytes stimulated through their antigen receptor (TCR) preferentially express mRNA isoforms with shorter 3' untranslated regions (3'-UTRs) derived from alternative pre-mRNA cleavage and polyadenylation (APA). However, the physiological relevance of APA programs remains poorly understood. CD5 is a T-cell surface glycoprotein that negatively regulates TCR signaling from the onset of T-cell activation. CD5 plays a pivotal role in mediating outcomes of cell survival or apoptosis, and may prevent both autoimmunity and cancer. In human primary T lymphocytes and Jurkat cells we found three distinct mRNA isoforms encoding CD5, each derived from distinct poly(A) signals (PASs). Upon T-cell activation, there is an overall increase in CD5 mRNAs with a specific increase in the relative expression of the shorter isoforms. 3'-UTRs derived from these shorter isoforms confer higher reporter expression in activated T cells relative to the longer isoform. We further show that polypyrimidine tract binding protein (PTB/PTBP1) directly binds to the proximal PAS and PTB siRNA depletion causes a decrease in mRNA derived from this PAS, suggesting an effect on stability or poly(A) site selection to circumvent targeting of the longer CD5 mRNA isoform by miR-204. These mechanisms fine-tune CD5 expression levels and thus ultimately T-cell responses.
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