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Professor of Pharmacology and Cancer Biology
Associate Professor of Radiation Oncology
Duke University School of Medicine
Durham, NC 27710
My laboratory studies the regulatory functions of protein acetylation in cell signaling and human disease. We focus on a class of protein deacetylases, HDACs, which we have discovered versatile functions beyond gene transcription. We wish to use knowledge of HDAC biology to develop smart and rational clinical strategies for HDAC inhibitors, a growing class of compounds that show potent anti-tumor and other clinically relevant activities. Currently, there two major research major areas in the laboratory: aging/age-related disease, and mitochondrial biology/cancer metabolism.
(1) Quality control (QC) autophagy in aging and neurodegenerative disease. The accumulation of damaged proteins and mitochondria is prominently linked to aging and age-associated disease, including neurodegeneration, metabolic disorders and cancer. Autophagy has emerged as specialized degradation machinery for the disposal of damaged protein aggregates and mitochondria, two common denominators in neurodegenerative diseases. We have discovered that this form of quality control (QC) autophagy is controlled by a ubiquitin-binding deacetylase, HDAC6. Using both mouse and cell models, we are investigating how HDAC6 enforces QC autophagy and its importance in neurodegenerative disease and metabolic disorders. The potential of HDAC6 as a therapeutic target is being actively pursued.
(2) HDAC in mitochondria function and quality control. Acetyl-CoA is the donor of acetyl group for protein acetylation and numerous metabolic reactions. Remarkably, many mitochondrial enzymes and proteins are subject to acetylation. We are interested in characterizing the roles of HDAC in mitochondrial adaptation to changing metabolic demands and elucidating the intimate relationship between metabolism and protein acetylation.
(3) HDAC, skeletal muscle remodeling, regeneration and neuromuscular disease. Skeletal muscle undergoes active remodeling in response to change in neural inputs or damage. Loss in neural input causes dramatic muscle dysfunction and disease, such as ALS. We have discovered that neural activity controls muscle phenotype through HDAC4, whose activity becomes deregulated in ALS patients. We have characterized this novel HDAC4-dependent signaling pathway and are evaluating modulators of this pathway for potential clinical utility in motor neuron disease.
Hubbert, C., Guardiola, A., Shao, R., Kawaguchi, Y., Ito, A., Yoshida, M., Wang, X.F. and Yao, T.-P. Identification of HDAC6 as a microtubule-associated deacetylase. Nature 417, 455-458 (2002)
Ito, A. Kawaguchi, Y., Lai, C.-H, Kovacs, J. J., Higashimoto, Y., Appella, E., and Yao, T.-P. MDM2-HDAC1 mediated-deacetylation of p53 is required for its degradation. EMBO. J. 22. 6236-6245 (2002)
Kawaguchi, Y., Kovacs, J. J., McLaurin, A., Vance, J. M., Ito, A., and Yao, T.-P. . The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell. 115. 727-738 (2003)
Kovacs, J.J., Murphy, P. J., Stéphanie Gaillard, Zhao, X., , Wu, J.-T., Nicchitta, C., Yoshida, M., Toft, D., Pratt, W., and Yao, T.-P. The deacetylase HDAC6 regulates Hsp90 acetylation and chaperone -dependent activation of glucocorticoid receptor. Molecular Cell 18(5) 601-607 (2005)
Cohen, T. J., Waddell, D., Barrientos, T., Lu, Z., Feng, G., Cox, G., Bodine, S., and Yao, T.-P., The histone deacetylase HDAC4 connects neural activity to muscle transcriptional reprogramming J. Biol. Chem. 282(46):3375-33759 (2007).
Gao, Y.-S., Hubbert, C., Lee, Y.-S., Kovacs, J. J., Lu, J., and Yao, T.-P. The microtubule-associated deacetylase HDAC6 regulates growth factor induced actin cytoskeleton remodeling and macropinocytosis. Mol Cell Biol. 27, 8637-8647 (2007).
Lee, J.-Y., Koga, H., Kawaguchi, Y., Wong, E., Tang, W., Pandey, U., Gao, Y-S., Lu, J., Taylor, J. P., Cuervo, A. M., and Yao, T.-P. HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality control autophagy. EMBO J. 29, 969-980 (2010).
Lee, J.-Y., Nagano, Y., Taylor, J.P., Lim, K.L., and Yao T.-P. Disease-causing mutations in Parkin impair mitochondrial ubiquitination, aggregation and HDAC6-depenent mitophagy. J. Cell Biol. 189 (4) 671-679 (2010).
Choi, M.-C., Cohen,T.J., Barrientos, T., Wang, B., M., Simmons, B.J., Yang, J.S., Cox, G. A., Zhao, Y.-M. and Yao, T-P.# A direct HDAC4-MAP kinase crosstalk activates neurogenic muscle atrophy. Molecular Cell, 47(1) 122-132 (2012).
Hao, R., Nanduri, P., Rao, Y., R. Scott Panichelli, R.S., Ito, A., Yoshida, M., and Yao, T.-P. Proteasomes activate aggresome disassembly and clearance by producing unanchored ubiquitin chains. Molecular Cell, In Press (2013)