Alternative splicing of FKBP5 gene exerts control over T lymphocyte expansion

Abstract

FKBP51 is constitutively expressed by immune cells. As other FKBP family members, FKBP51 acts as a coreceptor for the natural products FK506 and rapamycin, which exhibit immunosuppressive effects. However, little is known about the intrinsic role of this large FKBP in the primary function of lymphocytes, that is, the adaptive immune response against foreign antigens, for example, pathogens. This paper aimed to investigate whether FKBP51 expression was modulated during lymphocyte activation. Moreover, as we recently identified a splicing isoform of FKBP51, namely FKBP51s, we also measured this splice protein, along with the canonical one, at different times of a peripheral blood mononuclear cell culture stimulated via T cell receptor. Our results show that the two FKBP51 isoforms were alternatively induced during the proliferative burst. Canonical FKBP51 increased in the time window between 48 and 96 h and its expression levels correlated with cyclin D levels. FKBP51s transiently increased earlier, at 24−36 h to reappearing later, at 120 h, when cyclin D expression returned at resting levels and proliferation ceased. Interestingly, within these two specific timeframes, FKBP51s accumulated in the nucleus. Here FKBP51s colocalized with the Foxp3 transcription factor at 36 h. Regulatory T cell (Treg) counts significantly decreased when FKBP51s was downmodulated. The coculture suppression assay suggested that FKBP51s supports the suppressive capability of Tregs. At 120 h, chromatin immunoprecipitation experiments found FKBP51s linked to CCND1 gene, suggesting a possible effect on gene transcription regulation, as previously demonstrated in melanoma. In conclusion, our study shows that FKBP5 isoforms are upregulated during lymphocyte activation, albeit on different timeframes. The activation of canonical FKBP51 coincides with proliferation hallmarks; FKBP5 splicing occurs early to sustain Treg development and late when proliferation ceases.

Differential Dynamics and Roles of FKBP51 Isoforms and Their Implications for Targeted Therapies

“…The faster dynamic that we observe in blood samples compared to HeLa cells, with a return to baseline levels after 23 hours of Dex intake, is most probably due to a metabolization of Dex that occurs in vivo but not in vitro (Menke et al, 2016). The general faster responsiveness of variant 4 mirrors the findings of Marrone and colleagues (Marrone et al, 2023a), albeit in a different context, where they observe a similar rapid response of variant 4 when stimulating T cell proliferation as compared to variant 1. Notably, the authors also report a nuclear localization of variant 4, which aligns with our own observations (Fig.…”

“…The FK506 binding protein 51 (FKBP51) is a ubiquitously expressed immunophilin, encoded by the gene FKBP5, and whose function has been investigated in association with numerous biological processes describing FKBP51 as a central regulator of pathways involved in psychiatric and neurodegenerative disorders, immune response, inflammation, cardiovascular diseases, metabolic pathways and cancer (Zannas et al, 2016;Blair et al, 2015;Marrone et al, 2023b;Smedlund et al, 2021;Zannas et al, 2019). The most investigated role of FKBP51, is its involvement in the regulation of the stress response, initially discovered in squirrel monkeys where it was observed that an increased expression of FKBP51 is the cause of glucocorticoid receptor (GR) resistance and high circulating cortisol levels in these animals (Denny et al, 2000;Scammell et al, 2001).…”

Scaffold proteins of cancer signaling networks: The paradigm of FK506 binding protein 51 (FKBP51) supporting tumor intrinsic properties and immune escape

“…A caveat is, however, envisaged. FKBP51, whether on the one hand is aberrantly expressed by the tumor cells, on the other hand, is constitutively expressed in immune cells with a role in immune activation and proliferation [ 40 ]. Thus, as it occurs for many anticancer drugs, FKBP51-targeted therapy can impact the immune system, which deserves careful assessment in clinical trials.…”

“…Due to its multiple interactors for which we refer to Hähle et al [ 35 ], FKBP51 has pleiotropic functions and regulates numerous fundamental aspects of cell biology and physiology of living organisms, including development [ 36 ], differentiation [ 37 , 38 ] metabolism [ 39 ], response to hormones [ 32 ] and immune response [ 40 ]. Our review focuses on the scaffold roles of FKBP51 involved in signal transduction pathways and genetic and epigenetic regulation that drive cancer initiation and progression.…”