PRMT1 negatively regulates activation-induced cell death in macrophages by arginine methylation of GAPDH.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is implicated in cell death in addition to a role as a glycolytic enzyme. In particular, when cells are exposed to cellular stressors involving nitric oxide (NO) production, GAPDH can undergo NO-induced S-nitrosylation and S-nitrosylated GAPDH has been shown to elicit apoptosis. However, the mechanism underlying the regulation of the pro-apoptotic function of GAPDH remains unclear. Here, we found that protein arginine methyltransferase 1 (PRMT1) mediated arginine methylation of GAPDH in primary bone marrow-derived macrophages in a NO-dependent manner. Moreover, PRMT1 inhibited S-nitrosylation of GAPDH as well as its binding to SIAH1, thereby reducing the nuclear translocation of GAPDH in lipopolysaccharide (LPS)/interferon (IFN)-γ-activated macrophages. Furthermore, depletion of PRMT1 expression by RNA interference potentiated LPS/IFN-γ-induced apoptosis in macrophages. Taken together, our results suggest that PRMT1 has a previously unrecognized function to inhibit activation-induced cell death of macrophages through arginine methylation of GAPDH.

MST1 deficiency promotes B cell responses by CD4+ T cell-derived IL-4, resulting in hypergammaglobulinemia.

MST1 deficiency causes T and B cell lymphopenia, resulting in combined immunodeficiency. However, MST1-deficient patients also exhibit autoimmune-like symptoms such as hypergammaglobulinemia and autoantibody production. Recent studies have shown that the autoimmune responses observed in MST1-deficient patients were most likely attributable to defective regulatory T (Treg) cells instead of intrinsic signals in MST1-lacking B cells. Nevertheless, it is not determined how MST1 deficiency in T cells breaks B cell tolerance and causes systemic autoimmune-like phenotypes. In this study, we confirmed that Mst1-/- mice developed hypergammaglobulinemia associated with increased levels of IgG, IgA, and IgE. We also showed that uncontrolled B cell responses were resulted from the IL-4-rich environment created by CD4+ T cells. Defective MST1-FOXO1 signaling down-regulated Treg cells, resulting in the collapse of immune tolerance where the populations of Th2 and T follicular helper cells expanded. In conclusion, we suggest that MST1 acts as a molecular brake to maintain immune tolerance by regulating T cell-mediated B cell activation.

Protocol for the trismus trial-therabite versus wooden spatula in the amelioration of trismus in patients with head and neck cancer: randomised pilot study.

INTRODUCTION: Patients can develop trismus from their head and neck cancer or as a result of treatment. Trismus affects the jaw muscles and makes mouth opening difficult. To potentially combat trismus, patients could undertake proactive jaw stretching exercises prior to, during and after radiotherapy, although currently these are not the standard of care. METHODS AND ANALYSIS: This is a randomised, open-label, controlled, two-centre feasibility study, to assess the objective and subjective effectiveness and cost-effectiveness of therabite use compared with wooden spatula in ameliorating trismus in patients treated for stage 3 and 4 oral and oropharyngeal cancer, managed either by primary surgery followed by (chemo)radiotherapy or primary (chemo)radiotherapy. The principal objective assessment is measurement of maximum jaw opening. Assessments in all cases will be performed preradiotherapy and again at 3 and 6 months postintervention.Secondary aims of the study will be (1) to assess whether therabite or the wooden spatula intervention improves patients' quality of life, (2) reduce the level of post-treatment clinical management/healthcare use and (3) a nested qualitative study will explore the experience of the patient taking part in the intervention; data will be transcribed verbatim and analysis will be based on content analysis methods using the interview questions as the framework for examination. ETHICS AND DISSEMINATION: North West Greater Manchester granted ethical approval (REC Reference 11/NW/0744). Good Clinical Practice and the Declaration of Helsinki have been adhered to. The results will be presented internationally and submitted to a peer-reviewed journal. Head and neck cancer charities and information websites will also be approached. TRIAL REGISTRATION NUMBER: NCT01733797.