The cold shock protein YB-1 (Y-box protein-1) in chronic T cell responses and systemic lupus erythematosus (SLE)

• Applicant: Professorin Dr. Monika Christine Brunner-Weinzierl
• Subject Area: Rheumatology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 292779965

In the proposed study, the role of the cold shock protein YB-1 (Y-box protein-1) will be evaluated for modulating systemic lupus erythematosus (SLE) which is driven by chronic inflammation. Currently, there is no cure available. Alterations in T-cell homeostasis have been suggested to play a key role in the pathogenesis. In our previous work, we have identified YB-1 as a central molecule to drive proliferation and apoptosis of primary and malignant T cells. We showed that nuclear YB-1 is required to induce proliferation and survival. Its protein phosphorylation and subsequent translocation from the cytoplasm into the nucleus is dependent on the Rsk kinase. Inactivation of YB-1 using shRNA induced cell cycle arrest and, at least partially, abrogated cell survival. Data from SLE patients revealed that YB-1 is reduced upregulated in CD4 T cells upon T-cell activation, correlating with altered cytokine synthesis, enhanced apoptosis, and reduced cell proliferation rates. In addition, Cre-induced depletion of YB-1 in T cells led to high titers of anti-nuclear autoantibodies in a lupus-like mouse model.In the proposed project, the impact and molecular mechanisms that YB-1 has on T-cell differentiation and its relevance for SLE pathology will be addressed. Using ectopic expression of YB-1 mutants in combination with YB-1 shRNA to down-regulate the expression of endogenous YB-1, we will assign regions of YB-1 to distinct signaling pathways and, ultimately, elucidate their contributions in the context of T-cell differentiation in SLE, such as polyfunctionality determined by cytokine coexpression upon T cell stimulation or terminal differentiation (apoptosis). In this respect, we will distinguish between the impact of nuclear and cytoplasmic YB-1 localization applied to peripheral blood T cells harvested from SLE patients by using lentiviral transduction to analyze their molecular and functional characteristics. Using the NZB/W mouse model for experimental SLE, we will use cell type-specific depletion of YB-1 using CD4-Cre-inducible YB-1-deleter mice, in order to determine YB-1´s role in T-cell differentiation in the course of the disease. Results will give comprehensive insights into the roles of YB-1 in T-cell homeostasis and differentiation to validate the option to target it for the selective immune modulation of SLE.

• DFG Programme: Research Grants