Boston Children's Hospital
Warren Alpert Bldg., Rm. 255
200 Longwood Ave.
Boston, MA 02115
Fax: 617 713-8620
The Lieberman lab studies cytotoxic T lymphocytes (CTL), key cells in the immune defense against viruses and cancer. When CTL recognize an infected or transformed cell, they release the contents of their cytolytic granules into the immune synapse formed with the target cell. These granules contain death-inducing serine proteases, called granzymes, and a pore-forming protein, perforin, which delivers them to the target cell. The lab has developed a new model for how perforin works. A major focus is studying the molecular pathways activated by the granzymes. Granzyme A, the most abundant CTL protease, induces a novel form of apoptosis that is independent of the caspase pathway and results in single stranded DNA nicks. The lab has identified novel mechanisms of mitochondrial and DNA damage activated by granzyme A. They found that Trex1, one of the DNases activated by granzyme A, also plays an important role in HIV infection, innate immunity and autoimmunity. Current work is examining how killer lymphocytes target intracellular bacteria, how immune-mediated apoptosis affects cellular RNA processing, and how some of the less well studied granzymes activate cell death.
The Lieberman laboratory also studies how microRNAs regulates normal cell differentiation and cancer. Another major focus is figuring out how RNA interference could be harnessed to develop drugs to treat or prevent viral infection and cancer, especially breast cancer. Her group was the first to show that RNA interference could be used for therapy. They have been able to use small RNAs to inhibit sexual transmission of herpes virus and HIV in mice. They are developing ways of targeting small RNAs into specific cell types, including immune cells, in vivo. They are currently using small RNAs to knockdown one gene at a time in human CD4+ cells in humanized mice to study the role of individual host genes in HIV transmission.
Martinvalet D, Dykxhoorn DM, Ferrini R and Lieberman J. Granzyme A cleaves a mitochondrial complex I protein to initiate caspase independent cell death. Cell 2008; 133:681-692.
Yan N, Regalado-Magdos, AD, Stiggelbout B, Lee-Kirsch MA and Lieberman J. The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1. Nature Immunol 2010; 11:1005-1013.
Wheeler LA, Trifonova R, Vrbanac V, Basar E, McKernan S, Xu Z, Seung E, Deruaz M, Dudek T, Einarsson JI, Yang L, Allen TM, Luster AD, Tager AM, Dykxhoorn DM and Lieberman J. CD4 aptamer-siRNA chimeras inhibit sexual transmission of HIV to human cervicovaginal explants and humanized mice. J Clin Invest 2011; 121:2401-2412.
Thiery J, Keefe D, Boulant S, Boucrot E, Walch M, Martinvalet D, Goping IS, Bleackley RC, Kirchhausen T and Lieberman J. Perforin pores in the endosomal membrane trigger release of granzyme B to the cytosol of target cells. Nature Immunol 2011; 12:770-777.
Petrocca F, Altschuler G, Tan SM, Mendillo ML, Yan H, Jerry DJ, Kung AL, Hide W, Ince TA and Lieberman J. A genome-wide siRNA screen identifies proteasome addiction as a vulnerability of basal-like triple-negative breast cancer cells. Cancer Cell 2013; 24:182-196.
Last Update: 1/6/2014