Adrian T Ting, PhD
- ASSOCIATE PROFESSOR | Medicine, Clinical Immunology
Research Topics:Anti-Tumor Therapy, Apoptosis/Cell Death, Autoimmunity, Cancer, Cellular Immunity, Cytokines, Immunology, Inflammation, Interferon, Lymphocytes, Macrophage, Proteases, Protein Kinases, Receptors, Signal Transduction, T Cells, Tumor Suppressor Genes, Viruses and Virology
Multi-Disciplinary Training AreasImmunology [IMM], Microbiology [MIC]
BA, Luther College
PhD, Mayo Clinic
Dept. of Genetics, Harvard Medical School
Regulation of cell survival and death by ubiquitination
Our lab is interested in understanding how a cell decides to survive or die in response to an extracellular cue. A key regulator in this decision making process is the conjugation of ubiquitin chains to intracellular signaling molecules, which alters the function of these molecules. We study how a ubiquitin-removing enzyme known as CYLD is a key toggle between survival and death.
of Research Studies:
Stimulation of TNF receptor 1 (TNFR1) leads to either cell survival or to cell death. We recently showed that Caspase 8, which was originally described as a pro-death signaling molecule, could also promote cell survival. Caspase-8 does so by cleaving and causing the degradation of CYLD, a tumor suppressor that removes lysine 63-linked polyubiquitin chains. By removing CYLD, Caspase 8 promotes cell survival by inhibiting the induction of a novel cell death process known as necroptosis. Retaining CYLD leads to necroptosis. Thus CYLD functions as a toggle between cell survival (when it is inactive) and cell death (when it is active). This live versus death toggle is also functional downstream of other immune receptors including antigen receptors and Toll-like receptors. A major effect in the lab is directed towards understanding how these immune receptors regulate thisCYLD-dependent toggle to determine cell fate and in turn, how this effects responses to microbial infections and tumor formation. Other pro-survival mechanisms also function in concert with cleavage to repress CYLD and we are currently characterizing these mechanisms. Our ultimate goal is to pharmacologically manipulate these cell fate-determining mechanisms to enhance anti-microbial and anti-tumor responses.
Garcia-Carmona Y, Cols M, Ting AT, Radigan L, Yuk FJ, Zhang L, Cerutti A, Cunningham-Rundles C. Differential induction of plasma cells by isoforms of human TACI. Blood 2015 Mar; 125(11).
Manganaro L, Pache L, Herrmann T, Marlett J, Hwang Y, Murry J, Miorin L, Ting AT, König R, García-Sastre A, Bushman FD, Chanda SK, Young JA, Fernandez-Sesma A, Simon V. Tumor suppressor cylindromatosis (CYLD) controls HIV transcription in an NF-κB-dependent manner. Journal of virology 2014 Jul; 88(13).
Jianjun Yang , Zhang R, Lu G, Shen Y, Peng L, Zhu C, Cui M, Wang W, Arnaboldi P, Tang M, Gupta M, Qi CF, Jayaraman P, Zhu H, Jiang B, Chen SH, He JC, Ting AT, Zhou MM, Kuchroo VK, Morse HC, Ozato K, Sikora AG, Xiong H. T cell–derived inducible nitric oxide synthase switches off Th17 cell differentiation. The Journal of experimental medicine 2013 Jul; 210(7).
Rosebeck S, Rehman AO, Apel IJ, Kohrt D, Appert A, O'Donnell MA, Ting AT, Du MQ, Baens M, Lucas PC, McAllister-Lucas LM. The API2-MALT1 fusion exploits TNFR pathway-associated RIP1 ubiquitination to promote oncogenic NF-κB signaling. Oncogene 2014 May; 33(19).
Blackwell K, Zhang L, Workman LM, Ting AT, Iwai K, Habelhah H. Two coordinated mechanisms underlie tumor necrosis factor alpha-induced immediate and delayed IκB kinase activation. Molecular and cellular biology 2013 May; 33(10).
O'Donnell MA, Hase H, Legarda D, Ting AT. NEMO inhibits programmed necrosis in an NFκB-independent manner by restraining RIP1. PloS one 2012; 7(7).
O'Donnell MA, Ting AT. NFκB and ubiquitination: partners in disarming RIPK1-mediated cell death [review]. Immunologic research 2012 Dec; 54(1-3).
O'Donnell MA, Perez-Jimenez E, Oberst A, Ng A, Massoumi R, Xavier R, Green DR, Ting AT. Caspase 8 inhibits programmed necrosis by processing CYLD. Nature cell biology 2011 Dec; 13(12).
Lu J, McEachern D, Sun H, Bai L, Peng Y, Qiu S, Miller R, Liao J, Yi H, Liu M, Bellail A, Hao C, Sun SY, Ting AT, Wang S. Therapeutic potential and molecular mechanism of a novel, potent, nonpeptide, Smac mimetic SM-164 in combination with TRAIL for cancer treatment. Molecular cancer therapeutics 2011 May; 10(5).
O'Donnell MA, Ting AT. RIP1 comes back to life as a cell death regulator in TNFR1 signaling [review]. The FEBS journal 2011 Apr; 278(6).
O'Donnell MA, Ting AT. Chronicles of a death foretold: dual sequential cell death checkpoints in TNF signaling [review]. Cell cycle (Georgetown, Tex.) 2010 Mar; 9(6).
Legarda-Addison D, Hase H, O'Donnell MA, Ting AT. NEMO/IKKgamma regulates an early NF-kappaB-independent cell-death checkpoint during TNF signaling. Cell death and differentiation 2009 Sep; 16(9).
Friedman CS, O'Donnell MA, Legarda-Addison D, Ng A, Cárdenas WB, Yount JS, Moran TM, Basler CF, Komuro A, Horvath CM, Xavier R, Ting AT. The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response. EMBO reports 2008 Sep; 9(9).
Yang J, Yang M, Htut TM, Ouyang X, Hanidu A, Li X, Sellati R, Jiang H, Zhang S, Li H, Zhao J, Ting AT, Mayer L, Unkeless JC, Labadia ME, Hodge M, Li J, Xiong H. Epstein-Barr virus-induced gene 3 negatively regulates IL-17, IL-22 and RORgamma t. European journal of immunology 2008 May; 38(5).
Legarda-Addison D, Ting AT. Negative regulation of TCR signaling by NF-kappaB2/p100. Journal of immunology (Baltimore, Md. : 1950) 2007 Jun; 178(12).
O'Donnell MA, Legarda-Addison D, Skountzos P, Yeh WC, Ting AT. Ubiquitination of RIP1 regulates an NF-kappaB-independent cell-death switch in TNF signaling. Current biology : CB 2007 Mar; 17(5).
Zhao Q, Yang M, Ting AT, Logothetis DE. PIP(2) regulates the ionic current of P2X receptors and P2X(7) receptor-mediated cell death. Channels (Austin, Tex.); 1(1).
Yang M, Hase H, Legarda-Addison D, Varughese L, Seed B, Ting AT. B cell maturation antigen, the receptor for a proliferation-inducing ligand and B cell-activating factor of the TNF family, induces antigen presentation in B cells. Journal of immunology (Baltimore, Md. : 1950) 2005 Sep; 175(5).
Zhang Y, Ting AT, Marcu KB, Bliska JB. Inhibition of MAPK and NF-kappa B pathways is necessary for rapid apoptosis in macrophages infected with Yersinia. Journal of immunology (Baltimore, Md. : 1950) 2005 Jun; 174(12).
He KL, Ting AT. Essential role for IKKgamma/NEMO in TCR-induced IL-2 expression in Jurkat T cells. European journal of immunology 2003 Jul; 33(7).
Goodkin ML, Ting AT, Blaho JA. NF-kappaB is required for apoptosis prevention during herpes simplex virus type 1 infection. Journal of virology 2003 Jul; 77(13).
He KL, Ting AT. A20 inhibits tumor necrosis factor (TNF) alpha-induced apoptosis by disrupting recruitment of TRADD and RIP to the TNF receptor 1 complex in Jurkat T cells. Molecular and cellular biology 2002 Sep; 22(17).