"The function of the immune system is well-balanced, with one arm defending invading pathogens, and the other arm protecting from self attack. Loss of control can cause disastrous consequences such as the development of autoimmune diseases. My mission is to investigate the molecular events in lymphocytes in both normal and dysregulated states." - Yun-Cai Liu, Ph.D.

Dr. Liu is currently a Member in the Division of Cell Biology at LIAI. Dr. Liu's research focuses on analyzing signaling molecules in biochemical events that are triggered by receptors on lymphocytes.

Dr. Liu received his Ph.D. in Cell Biology from Gunma University in Japan. Following his doctorate, Dr. Liu did research at the Kirin Brewery Co., Ltd. before coming to LIAI in 1993 for his postdoctoral training. In 1997 he became a research scientist at LIAI, and in 1999 he was appointed to the faculty as an Assistant Member.

Yun-Cai Liu, Ph.D and his team study the regulation of lymphocyte function by tagging a small peptide ubiquitin to protein targets and the implication of the ubiquitin system in abnormal immune responses such as autoimmune diseases or allergic asthma.

The process of ubiquitin conjugation to a protein substrate is carried out by sequential enzymatic reactions. When a protein is tagged with ubiquitin, it sends a signal for destruction by the garbage disposal machinery inside the cell. Timely removal of harmful or excessive proteins is critical to maintain normal cell function. Dysfunction in this system can result in a disease state such as cancer, or immunological diseases.

Work from Dr. Liu's team has established that Cbl family of adaptor proteins acts as E3 ubiquitin ligases, which facilitate the transfer of ubiquitin to a specific protein target. More recent work identified that one of this family proteins, Cbl-b, is essential to keep T cells under control. Loss of Cbl-b results in excessive T cell activation, which leads to the attack of self-tissues or organs such as the joints or pancreas, and the development of arthritis and diabetes.

Dr. Liu's team also discovered that another E3 ubiquitin ligase, Itch, is a critical regulator for the development of a specific subset of T cells, called T cell helper type 2, which are responsible for the production of allergic mediators. Loss of Itch results in abnormal excessive function of these cells, and in the development of allergic asthma. Further understanding of the ubiquitin system may add in designing therapeutic inventions for human diseases such as arthritis, diabetes, and asthma.

Mechanisms of NKT cell anergy induction involve Cbl-b-promoted monoubiquitination of CARMA1. Proc Natl Acad Sci USA. 2009

The E3 ubiquitin ligase Itch regulates expression of transcription factor Foxp3 and airway inflammation by enhancing the function of transcription factor TIEG1.  Nat Immunol. 2008

Negative Regulation of the E3 Ubiquitin Ligase Itch via Fyn-Mediated Tyrosine Phosphorylation. Mol Cell. 2006

Immunity by ubiquitylation: a reversible process of modification. Nat Rev Immunol. 2005

Ubiquitin ligases and the immune response. Annu Rev Immunol. 2004

Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase Itch. Science. 2004

Itch E3 ligase-mediated regulation of TGF-Beta signaling by modulating Smad2 phosphorylation. Mol Cell. 2004

Essential Role of the E3 Ubiquitin Ligase Cbl-b in T Cell Anergy Induction. Immunity. 2004

Dysregulation of T lymphocyte function in itchy mice: a role for Itch in TH2 differentiation. Nat Immunol. 2002

The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase. Science. 1999

Proteolysis-independent regulation of phosphatidylinositol 3-kinase by Cbl-b-mediated ubiquitination in T cells. Nature Immunol. 2001

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