Jesús María Salvador
Group Leader
Research summary
The main goal of our group is to study the molecular mechanisms that regulate T cell signalling in the development of autoimmune diseases and cancer. We focus on the role of the Gadd45 (growth arrest and DNA damage-inducible genes) and p38 MAPK (mitogen-activated protein kinase) families in suppression of autoimmunity and cancer.
Publications
Salvador-Bernáldez M1, Mateus SB1, Del Barco Barrantes I2, Arthur SC3, Martínez-A C1, Nebreda AR2,4, Salvador JM. p38α regulates cytokine-induced IFNγ secretion via the Mnk1/eIF4E pathway in Th1 cells. Immunol Cell Biol. 2017 Jun 14. doi: 10.1038/icb.2017.51
Gonzalez-Martin A, Adams BD, Lai M, Shepherd J, Salvador-Bernaldez M, Salvador JM, Lu J, Nemazee D, Xiao C.The microRNA miR-148a functions as a critical regulator of B cell tolerance and autoimmunity. Nat Immunol. 2016 Feb 22. doi: 10.1038/ni.3385.
Salvador JM, Brown-Clay JD, Fornace AJ. Gadd45 in stress signalling, cell cycle control and apoptosis. Adv Exp Med Biol 2013; 793:1-19
Johnen H, González-Silva L, Carramolino L, Flores JM, Torres M, Salvador JM. Gadd45g is essential for primary sex determination, male fertility and testis development.PLoS ONE 2013; 8:e58751
Our group studies the biological functions of the Gadd45 and p38 MAPK (mitogen-activated protein kinase) families in the suppression and development of autoimmunity and cancer. Gadd45 proteins are characterised mainly as classical tumour suppressors that induce cell cycle arrest and apoptosis in response to DNA damage or oncogenic stimuli. They play key roles in a range of other physiological processes, including DNA demethylation and repair, maintenance of genomic stability through mitosis and immunological regulation and activation, although the molecular mechanisms involved in these functions are still under study.
We found an important role for Gadd45a in suppression of autoimmunity through regulation of CD4+ T cell functions. Whereas Gadd45 is typically associated with growth arrest in most cell types, p38 activation has a key stimulatory role in lymphocytes. p38 is necessary for T cell activation and Gadd45a is a major modulator of p38 in this process. Gadd45 acts as an autoimmune suppressor in vivo by negatively regulating T cell proliferation in response to TCR activation. Unlike Gadd45a, the Gadd45b and Gadd45g isoforms potentiate p38 signalling in Th1 and CD8+ cytotoxic T cells, which is necessary for full effector function. Gadd45b is necessary for full expression of the Th1 lineage-inducing protein T-bet. Gadd45 family members thus appear to work synergistically to promote full maturation and function of Th1 and CD8+ cells.
In addition to the role in suppression of autoimmunity, we identified an unanticipated function for Gadd45g, but not Gadd45a or Gadd45b, during embryonic development. Gadd45g expression is central to male fertility, testis development and sex determination. Gadd45g-deficientmicer showed an unexpected male-to-female sex reversal phenotype. We found that Gadd45g is necessary for SRY expression and that lack of Gadd45g blocks SOX9, resulting in ovary development. The genetic basis of human male-to-female sex reversal remains unexplained in the majority of cases. Our results identify Gadd45g as a candidate gene in human non-syndromic male infertility and in partial or complete male-to-female primary sex reversal in 46, XY individuals.
