Identification of a novel epigenetic module in immune regulation, autoimmunity and antitumor immune response.
Research in Fang laboratory has focused on the molecular mechanisms of immune regulation, inflammation and cancer for more than 20 years. In particular, our long-term research goal is to gain a better understanding of the molecular mechanisms behind peripheral T cell tolerance. Since Sir Frank Macfarlane Burnet first described immune tolerance in late 1950s and received the 1960 Nobel Prize in Physiology or Medicine. Since then tremendous efforts have identified genes that are responsible for T cell tolerance, however the particular molecular mechanisms underlying peripheral T cell tolerance remain an immunological mystery. We have identified the type III histone deacetylase Sirt1 as an essential factor to maintain immune tolerance to self-antigens (Journal of Clinical Investigation, 2009), and shown IL-2-mediated suppression of Sirt1 expression resulted in the breakdown of T cell peripheral tolerance (PNAS, 2011). These findings from my laboratory lead to a better understanding of the molecular mechanisms in antigen-specific immune responses and the development of autoimmune diseases such as multiple sclerosis, type 1 diabetes and lupus. Using a proteomic approach, we identified that the ubiquitin-specific peptidase 22 (USP22) as a Sirt1-specific deubiquitinase (Molecular Cell, 2012). USP22 deficiency leads to myeloid leukemia upon oncogenic K-Ras activation through a PU.1-dependent mechanism (Blood, 2018). More importantly, we further discovered that USP22 promotes Foxp3 gene transcription through suppressing histone 2B monoubiquitination and protects FoxP3 protein from ubiquitination-mediated degradation (Nature, 2020). In addition, targeted USP22 gene deletion largely abolishes iNKT cell immunity and USP22 controls iNKT cell development and differentiation through the mediator complex 1 (Med1)-mediated suppression of histone 2A monoubiquitination (Journal of Experimental Medicine, 2020). Our laboratory is currently dissecting the molecular networks associated with the Sirt1-USP22 epigenetic module in immune regulation, inflammation and antitumor immunity.