Sumoylation, the covalent attachment of small ubiquitin-like modifier (SUMO) to cellular proteins, has emerged as an important signaling mechanism for regulating protein activity, stability/degradation, subcellular localization, and protein-protein interaction. Like ubiquitination, sumoylation is a dynamic and reversible post-translational modification that is controlled by opposing actions of sumoylating enzymes and SUMO proteases (also known as desumoylating enzymes). Sumoylation plays a critical role in regulation of numerous cellular processes, from transcriptional regulation and DNA repair to protein trafficking, mitochondrial dynamics, and apoptosis. Dysregulated sumoylation has been implicated in a variety of human diseases, including cancer, diabetes, heart disease, and neurodegenerative disorders such as Alzheimer and Parkinson diseases. Despite increasing evidence supporting the importance of sumoylation to human health and disease, our knowledge about the sumoylation/desumoylation machinery components and their cellular functions is limited. In this project, the applicant's team will use a combination of biochemical, proteomic, cell biological, and mouse genetic approaches to study a novel SUMO protease and its signaling role in cellular defense against oxidative stress and apoptosis. The results of the proposed studies should advance our knowledge of the fundamental mechanisms governing SUMO signaling in all eukaryotic cells and provide a molecular basis for understanding and treating a diverse array of human diseases that involve dysregulated sumoylation.
The importance of proper sumoylation to human health is highlighted by the evidence linking dysregulated sumoylation to a variety of human diseases, including cancer, diabetes, heart disease, and neurodegenerative disorders such as Alzheimer, Parkinson, and Huntington diseases. The goal of the proposed research is to understand, at the molecular level, how sumoylation is controlled in normal physiology and how this process becomes dysregulated in disease states. The results of the proposed studies will provide fundamental information needed for the development of effective therapeutics to treat diverse human diseases in which protein sumoylation is disturbed.
|Zhang, Qi; Ma, Cheng; Gearing, Marla et al. (2018) Integrated proteomics and network analysis identifies protein hubs and network alterations in Alzheimer's disease. Acta Neuropathol Commun 6:19|
|Lee, Samuel M; Chin, Lih-Shen; Li, Lian (2017) Dysregulation of ErbB Receptor Trafficking and Signaling in Demyelinating Charcot-Marie-Tooth Disease. Mol Neurobiol 54:87-100|
|Yung, Cheryl; Sha, Di; Li, Lian et al. (2016) Parkin Protects Against Misfolded SOD1 Toxicity by Promoting Its Aggresome Formation and Autophagic Clearance. Mol Neurobiol 53:6270-6287|
|Shimizu, Yuuki; Lambert, Jonathan P; Nicholson, Chad K et al. (2016) DJ-1 protects the heart against ischemia-reperfusion injury by regulating mitochondrial fission. J Mol Cell Cardiol 97:56-66|
|Chin, Lih-Shen; Li, Lian (2016) Ubiquitin phosphorylation in Parkinson's disease: Implications for pathogenesis and treatment. Transl Neurodegener 5:1|
|McKeon, Jeanne E; Sha, Di; Li, Lian et al. (2015) Parkin-mediated K63-polyubiquitination targets ubiquitin C-terminal hydrolase L1 for degradation by the autophagy-lysosome system. Cell Mol Life Sci 72:1811-24|
|Fallaize, Dana; Chin, Lih-Shen; Li, Lian (2015) Differential submitochondrial localization of PINK1 as a molecular switch for mediating distinct mitochondrial signaling pathways. Cell Signal 27:2543-54|
|Lee, Samuel M; Sha, Di; Mohammed, Anum A et al. (2013) Motor and sensory neuropathy due to myelin infolding and paranodal damage in a transgenic mouse model of Charcot-Marie-Tooth disease type 1C. Hum Mol Genet 22:1755-70|
|Chin, Lih-Shen; Lee, Samuel M; Li, Lian (2013) SIMPLE: A new regulator of endosomal trafficking and signaling in health and disease. Commun Integr Biol 6:e24214|