Maia Ludmila Budziñski.
Romina P. Gobbini, Clara Sokn, Belén Ugo.
The activation of inflammatory pathways in response to stress in the central nervous system (SNC) plays a key role in neuroendocrine processes. Depression is associated with clinical settings that present an inflammatory component together with an altered function of the hypothalamic-pituitary-adrenal (HPA) axis, showing increase glucocorticoid secretion altered inhibitory feedback of the HPA axis and increased inflammatory cytokine levels.
The activity of the glucocorticoid receptor (GR) is regulated by a multiprotein complex, which includes the co-chaperone FKBP (FK506 binding protein) 51, an inhibitor of GR whose functional alterations are associated with immune and inflammatory diseases, and with depression. Due to its interaction with Hsp90 and Akt, FKBP51 is also linked to the development of neurodegenerative diseases, the modulation of autophagy mediated by antidepressants, and the regulation of cellular metabolism.
Study of the role of SUMOylation as a regulator of the glucocorticoid receptor and co-chaperones activity in stress and inflammation
We study how post-translational modifications (PTMs), particularly SUMOylation, impact on the regulation of the activity of these proteins under basal, or cellular and systemic stress conditions and the consequences of this modulation. Given the need to design new strategies for the treatment of disorders that involve an alteration in the function of the GR, this research line could lead to the identification of new therapeutic targets and molecules for the treatment of these pathologies.
Study of the signaling pathways regulated by activation of P2X7 receptor and its functional relation with PARP1 and the glucocorticoid receptor in the inflammatory context
We study how the PTM PARylation and its effector PARP1, which has a central role in the regulation of the immune and inflammatory response at the central level in normal neuronal function and in several neurodegenerative processes, interact with the GR. Both share common signalling pathways but have antagonistic roles in the regulation of inflammatory processes that are key to the effective maintenance of homeostasis, and their interaction could be relevant to maintain neuroendocrine circuits.
In particular, since we found PARP1 in the signaling pathway mediated by the activation of the P2X7 receptor (P2X7R), a ion channel involved in the regulation of inflammatory processes and depression, our aim is to characterize the mechanisms that involve PARP1 in the signaling pathway of P2X7R and its impact on GR activity in inflammatory processes within the CNS.
Publications related to this project
- Deussing JM, Arzt E.
P2X7 Receptor: A Potential Therapeutic Target for Depression?
Trends Mol Med, 24:736-747, 2018.
- Antunica-Noguerol, M., Budziñski, ML., Druker, J., Gassen, NC., Sokn, MC., Senin, S., Aprile-Garcia, F., Holsboer, F., Rein, T., Liberman, AC.*, Arzt, E*.
The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51.
Cell Death Differ. 23:1579-91 (2016)
- Druker, J.; Liberman, A.C.; Antunica Noguerol, M.; Gerez, J.; Paez Pereda, M.; Rein, T.; Iñiguez Lluhí, J.A.; Holsboer, F., Arzt, E.
RSUME enhances Glucocorticoid Receptor SUMOylation and transcriptional activity.
Molecular and Cellular Biology 33:2116-27 (2013)
- Liberman, A., Refojo, D., Antunica Noguerol, M., Holsboer, F., Arzt, E.
Underlying mechanisms of cAMP- and glucocorticoid-mediated inhibition of FasL expression in activation-induced cell death.
Molecular Immunology. 50:220-35 (2012)
- Liberman AC, Castro CN, Barcala Tabarrozzi A, Druker J, Antunica Noguerol M, Perone MJ Arzt E.
Molecular mechanisms of glucocorticoids action: from basic research to clinical implications.
Current Immunology Reviews 6:371-380 (2010)
- Liberman AC, Druker J, Refojo D, Holsboer F., Arzt E.
Glucocorticoids inhibit GATA-3 phosphorylation and activity in T cells.
FASEB J. 23:1558-71 (2009)
- Liberman AC, Refojo D, Druker J, Toscano MA, Rhein T, Holsboer F., Arzt E.
The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction.
FASEB J. 21:1177-88 (2007)