Junying Yuan

Department of Cell Biology
Harvard Medical School
Seeley G. Mudd Building, Room 400
250 Longwood Avenue
Boston, MA 02115
Tel: (617) 432-4170
Fax: (617) 432-4177
Email: jyuan@hms.harvard.edu
Web Page: The Yuan Lab Page
9 postdoctoral fellows, 4 graduate students

Our laboratory studies the mechanisms of cell death. We study the pathways of apoptotic as well as non-apoptotic cell death. We are interested in understanding how cancer cells evade apoptotic checkpoints and how mutant proteins involved in neuronal degenerative diseases activate cell death mechanisms. The tools that we use include cell biology, genetics, biochemistry and chemical biology. The research in our lab can be divided into 3 major areas:

1. Regulation of apoptosis and inflammation by caspases.
Caspase-11 is an important pro-inflammatory caspase essential for the activation of caspase-1 and processing of IL1b upon LPS stimulation. Our recent work led to the unexpected finding that caspase-11 regulates cell migration by interacting with Aip1 that promotes cofilin mediated actin depolymerization under inflammatory condition. The ongoing work in this area concentrates on another actin binding protein that interacts with caspase-11 that can regulate the activity and subcellullar localization of caspase-11. These experiments may reveal the dynamic interaction of actin cytoskeleton with caspases.

2. Regulation of autophagy.
Autophagy is a cellular mechanism mediating bulk turnover of cellular proteins and intracellular organelles. Selective activation of autophagy is effective in removing misfolded proteins. We study non-starvation regulation of autophagy because although many mammalian homologues of yeast autophagy genes have been identified, very little is known about the regulation of autophagy beyond starvation response. Our finding has implications in cell cycle regulation of autophagy under physiological conditions as well as in neurodegeneration.

3. The molecular mechanism of necroptosis, a programmed necrotic cell death pathway.
Although necrosis is known as a type of passive cell death caused by overwhelming stress, we found that when death receptor mediated apoptosis fails to occur, cells might die instead with typical features of necrosis which we termed necroptosis. We identified a series of small molecules that can selectively inhibit necroptosis. These small molecules target known as well as novel targets of necroptosis. We are using these small molecules as tools to explore the mechanism of necroptosis.

Potential rotation projects include learning about how to distinguish apoptotic and non-apoptotic cell death using cell biological and chemical biological tools, characterize the mechanisms of caspase activation, investigate the relationship of autophagy and cell death, etc.

References:

• Boyce M, Bryant KF, Jousse C, Long K, Harding HP, Scheuner D, Kaufman RJ, Ma D., Coen DM, Ron D and Yuan J. A Selective Inhibitor of eIF2alpha Dephosphorylation Protects Cells from ER Stress. Science. 2005. 307, 935-939.
• Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, Cuny GD, Mitchison TJ, Moskowitz MA and Yuan J. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nature Chemical Biology. 2005. 1, 112-119.
• Li J, Brieher WM, Scimone ML, Kang SJ, Zhu H, Yin H, von Andrian UH, Mitchison T, Yuan J. Caspase-11 regulates cell migration by promoting Aip1-Cofilin-mediated actin depolymerization. Nat Cell Biol. 2007. 9, 276-86.