Prof. Shao-Cong Sun’s laboratory discovered an ubiquitin-dependent epigenetic mechanism that regulates inflammation
Source：Shao-Cong Sun
2016-04-04
The laboratory of professor Shao-Cong Sun at the University of Texas MD Anderson Cancer Center discovered an epigenetic mechanism by which ubiquitination regulates toll-like receptor (TLR)-stimulated IL-12 and IL-23 gene expression in dendritic cells (DCs), and, thereby, promotes the generation of inflammatory T cells. This work, published in the March 2016 issue of Nature Immunology, was led by a former postdoctoral fellow of the lab, Dr. Jin Jin, who is now a professor in Zhejiang University, as well as a current postdoctoral fellow, Dr. Xiaoping Xie.
Dendritic cells (DCs) are the primary antigen-presenting cells that play a crucial role in initiating immune responses against infections. In response to an infection, DCs recognize pathogens via various pattern-recognition receptors (PRRs), including members of the TLR family. The PRR signals stimulate DCs to secrete a plethora of cytokines and undergo maturation to become competent antigen-presenting cells. Mature DCs present microbial antigens to naïve T cells to induce the expansion of pathogen-specific T cells. Under the influence of the DC-derived cytokines, activated CD4+ T cells differentiate into several subsets of effector T cells, including T helper (Th)1, Th2, Th17, and T follicular (Tfh) cells. While normal production of effector T cells is required for clearance of the pathogens, deregulated production of effector T cells contributes to the development of immunological disorders. In particular, the Th1 and Th17 subsets of inflammatory T cells are associated with several inflammatory diseases, including the neuroinflammatory disease multiple sclerosis. Generation of Th1 and Th17 cells is largely regulated by the cytokines IL-12 and IL-23 that are produced by DCs and other innate immune cells, but the molecular mechanism underlying IL-12/IL-23 gene induction is incompletely understood.
The Sun lab discovered an ubiquitin-dependent mechanism that controls epigenetic changes involved in the induction of IL-12 and IL-23 genes by TLRs. A central component of this signaling mechanism is a deubiquitinase (DUB), Trabid, which belongs to the A20 subfamily of OTU domain-containing DUBs. Trabiddeubiquitinates and stabilizes a histone demethylase, Jmjd2d, which in turn is required for regulating histone methylation and promoting recruitment of transcription factor NF-kB to the promoter regions of IL-12 and IL-23 genes. Trabid deficiency in DCs causes a dramatic reduction in the level of Jmjd2d, resulting in attenuated IL-12/IL-23 gene induction. Consequently, the Trabid-deficient mice have impaired production of Th1 and Th17 cells and become refractory to the induction of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. These findings reveal a novel mechanism regulating IL-12/IL-23 gene induction and implicate Trabid and Jmjd2d as potential therapeutic targets for the treatment of inflammatory diseases, such as multiple sclerosis.
Professor Sun is known for his many contributions to the fields of NF-kB and ubiquitination. The present work represents another major contribution of the Sun lab to these exciting fields. Previous studies on ubiquitination have focused on the regulation of signal transduction leading from immune receptors to activation of transcription factors, such as NF-κB. The present finding by professor Sun’s lab highlights the importance of ubiquitination in the control of epigenetic events involved in TLR signaling and inflammatory responses. This finding is likely to have a major impact in a broad area of Immunology research, including TLR signaling, ubiquitination, and inflammation.
Dendritic cells (DCs) are the primary antigen-presenting cells that play a crucial role in initiating immune responses against infections. In response to an infection, DCs recognize pathogens via various pattern-recognition receptors (PRRs), including members of the TLR family. The PRR signals stimulate DCs to secrete a plethora of cytokines and undergo maturation to become competent antigen-presenting cells. Mature DCs present microbial antigens to naïve T cells to induce the expansion of pathogen-specific T cells. Under the influence of the DC-derived cytokines, activated CD4+ T cells differentiate into several subsets of effector T cells, including T helper (Th)1, Th2, Th17, and T follicular (Tfh) cells. While normal production of effector T cells is required for clearance of the pathogens, deregulated production of effector T cells contributes to the development of immunological disorders. In particular, the Th1 and Th17 subsets of inflammatory T cells are associated with several inflammatory diseases, including the neuroinflammatory disease multiple sclerosis. Generation of Th1 and Th17 cells is largely regulated by the cytokines IL-12 and IL-23 that are produced by DCs and other innate immune cells, but the molecular mechanism underlying IL-12/IL-23 gene induction is incompletely understood.
The Sun lab discovered an ubiquitin-dependent mechanism that controls epigenetic changes involved in the induction of IL-12 and IL-23 genes by TLRs. A central component of this signaling mechanism is a deubiquitinase (DUB), Trabid, which belongs to the A20 subfamily of OTU domain-containing DUBs. Trabiddeubiquitinates and stabilizes a histone demethylase, Jmjd2d, which in turn is required for regulating histone methylation and promoting recruitment of transcription factor NF-kB to the promoter regions of IL-12 and IL-23 genes. Trabid deficiency in DCs causes a dramatic reduction in the level of Jmjd2d, resulting in attenuated IL-12/IL-23 gene induction. Consequently, the Trabid-deficient mice have impaired production of Th1 and Th17 cells and become refractory to the induction of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. These findings reveal a novel mechanism regulating IL-12/IL-23 gene induction and implicate Trabid and Jmjd2d as potential therapeutic targets for the treatment of inflammatory diseases, such as multiple sclerosis.
Professor Sun is known for his many contributions to the fields of NF-kB and ubiquitination. The present work represents another major contribution of the Sun lab to these exciting fields. Previous studies on ubiquitination have focused on the regulation of signal transduction leading from immune receptors to activation of transcription factors, such as NF-κB. The present finding by professor Sun’s lab highlights the importance of ubiquitination in the control of epigenetic events involved in TLR signaling and inflammatory responses. This finding is likely to have a major impact in a broad area of Immunology research, including TLR signaling, ubiquitination, and inflammation.
