CD5 expression is regulated during human T‐cell activation by alternative polyadenylation, PTBP1, and miR‐204

Abstract

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.

Identification and Characterization of Transcripts Regulated by Circadian Alternative Polyadenylation in Mouse Liver

“…, CSTF77 and NUDT21, are expressed rhythmically in mouse liver ( Mauvoisin et al 2014 ; Robles et al 2014 ), it is tempting to speculate that they are involved in regulating circadian APA at least for some genes. Changes in the levels of the other core components for cleavage and polyadenylation machinery, including CSTF-64/CSTG2, CSTF-64τ, CFI-68/CPSF6, CFI-25/CPSF5, FIP1L1, and PCF11 as well as auxiliary factors such as PABPN1, PTBP, RBBP6, and PAF1C, have all been shown to impact poly(A) site choices ( Takagaki et al 1996 ; Takagaki and Manley 1998 ; Kubo et al 2006 ; de Klerk et al 2012 ; Jenal et al 2012 ; Martin et al 2012 ; Yao et al 2012 ; Yao et al 2013 ; Di Giammartino et al 2014 ; Lackford et al 2014 ; Masamha et al 2014 ; Gennarino et al 2015 ; Li et al 2015 ; Domingues et al 2016 ; Yang et al 2016 ). These proteins may also be involved in regulating circadian APA, although this remains to be investigated.…”

Age-related transcriptional modules and TF-miRNA-mRNA interactions in neonatal and infant human thymus

“…Their expression is maximal in DP thymocytes, decreasing by 75-95% at later stages of T-cell development [28]. PTBP1 codifies for an RNA binding protein that plays a critical role in early T lymphocyte ontogeny by regulating the expression of CD5 and, consequently, TCR signaling [29]. Two other genes-CAND1 and UBE3B -are primarily related to ubiquitination and involved with mTECs and tolerance induction.…”

“…CD5 (tan module) codifies for a glycoprotein found on thymocyte's membrane and it is expressed early in T lymphocyte ontogeny functioning as negative regulator of TCR-mediated signaling, fine-tuning the TCR signaling response during thymocyte selection [32]. It is worth to note that CD5 expression is regulated by PTBP1 [29], an HGS gene in group A. SNX17 (green yellow module), also a hub gene, is involved in TCR trafficking and recycling [17]. SCLT1 (alias CAP-1A) codifies for a clathrin adaptor and is related to T-cell positive selection.…”

Immune System Sex Differences May Bridge the Gap Between Sex and Gender in Fibromyalgia

“…Fourthly, CD5 expression fine-tunes the adaptive immune response in a complex way (Sigal, 2012). CD5 on T or B lymphocytes may either facilitate or inhibit an adaptive immune response depending on avidity issues (Domingues et al, 2016). In general, CD5+ B cells have been related with increased susceptibility for autoimmune disease, while the opposite applies to T cells (Tarakhovsky et al, 1995;Pers et al, 1999;Hawiger et al, 2004).…”