My laboratory focuses on identifying and characterizing novel regulatory functions of protein acetylation in cell signaling and human disease. We wish to develop fundamental understandings of a class of protein deacetylases, HDACs, and use this knowledge to develop smart and rational clinical strategies based on HDAC inhibitors, a growing class of compounds that show potent anti-tumor and other clinically relevant activities. Currently, there are three major research areas in the laboratory:

(1) HDAC, quality control (QC) autophagy, and neurodegenerative disease. Autophagy has emerged as specialized degradation machinery for the disposal of protein aggregates and damaged mitochondria, two common denominators in neurodegenerative diseases. We have discovered that this so-called QC autophagy is controlled by a microtubule-associated, ubiquitin-binding deacetylase, HDAC6.  Using both mouse and cell models, we are investigating how HDAC6-regulated acetylation controls QC autophagy, and its importance in the pathogenesis and therapy of neurodegenerative disease.

(2) HDAC, mitochondria, and cancer metabolism. Acetyl-CoA is the donor of acetyl group in both protein acetylation and numerous metabolic reactions. Remarkably, many mitochondrial proteins are subject to acetylation. We are interested in understanding how HDAC and protein acetylation controls mitochondria function. We are also pursuing mitochondria- and tumor-specific metabolism as novel therapeutic targets in cancer treatment.

(3) HDAC, skeletal muscle remodeling, and neuromuscular disease. Skeletal muscle undergoes active remodeling in response to change in neural inputs. Loss in neural input causes dramatic muscle dysfunction and neuromuscular disease, such as ALS. We have discovered that neural activity controls muscle phenotype by a specific HDAC, whose activity becomes deregulated in ALS patients. We are characterizing this novel HDAC-dependent signaling pathway, and developing modulators of this pathway for their 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)

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)

Norris, K. L., Lee, J. Y. Yao, T. P. Acetylation goes global: the emergence of acetylation biology. Science Signal. 2 (97), pe76-80 (2009)

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. (In Press)