As the head of the Laboratory for Protein Characterization at the Technion, Professor Glickman hopes to gain insight into the cellular system that degrades proteins in a controlled manner. This system ensures that superfluous or defective proteins are marked with a molecular tag, the protein ubiquitin, and are disposed of in the cellular shredding machine, the proteasome. It is one of the organism’s most complex cellular systems and protects the body against serious diseases such as Alzheimer’s, Parkinson’s, Huntington’s, cystic fibrosis or diabetes. In addition to proteasome structure and function, his laboratory studies mechanistic aspects of protein degradation, charts the cellular ubiquitin-linkage profile using mass spectrometry and proteomics, analyses the importance of proteolysis in homeostasis and regulation of the proteome by the specific recognition of ubiquitin and ubiquitin-like proteins. A separate yet related project looks at the biology of mitochondria membrane fusion and fission. More specifically, how does ubiquitination and proteasome-dependent-degradation participate in mitochondria function and dynamics. Prevention of damage as well as quality control system to remove and replace damage as it accrues are are mechanisms which enable healthy living and graceful aging. Environmental assaults can exacerbate premature aging of proteins; these include oxidative damage, radiation (e.g. UV), heat, chemical reagents or toxins, and a slew of genomic mutations. Ironically, reactive oxidative species (ROS) that leach out from mitochondria – those little powerhouses within our cells that use oxygen to generate energy – are a major source of oxidative damage. Hence, the importance of anti-oxidants to detoxify the internal cellular environment.
A recent discovery from the laboratory of Professor Glickman at the Technion describes an unexpected reciprocal relationship between mitochondria and the protein removal machinery, which has novel implications for mitigating effects of aging.)
7. Ziv I, Matiuhin Y, Kirkpatrick DS, Erpapazoglou Z, Leon S, Pantazopoulou M, Kim W, Gygi SP, Haguenauer-Tsapis R, Reis N, Glickman MH*, Kleifeld O* (* corresponding), A perturbed ubiquitin landscape distinguishes between ubiquitin in trafficking and in proteolysis., Mol Cell Proteomics. 2011 May;10(5):M111.009753. Epub 2011 Mar 22.
8. Rosenzweig R, Bronner V, Zhang D, Fushman D, Glickman MH. Rpn1 and Rpn2 coordinate ubiquitin processing factors at the proteasome J Biol Chem. 2012 Apr 27;287(18):14659-71.
9. Singh RK, Zerath S, Kleifeld O, Scheffner M, Glickman MH*, Fushman D*, Recognition and Cleavage of Rub1 and Rub1-Ubiquitin Chains by Components of the Ubiquitin-Proteasome System. Mol Cell Proteomics. 2012 Dec;11(12):1595-611
10. Bagola K, von Delbrück M, Dittmar G, Scheffner M, Ziv I, Glickman MH, Ciechanover A, Sommer T. Ubiquitin Binding by a CUE Domain Regulates Ubiquitin Chain Formation by ERAD E3 Ligases. Mol Cell. 2013 May 23;50(4):528-39.
11. Livnat-Levanon Nurit, Kleifeld Oded, Kevei Éva, Krutauz Daria, Rinaldi Theresa, Segref Alexandra, Erpapazoglou Zoi, Cohen Mickael, Reis Noa, Hoppe Thorsten, and Glickman Michael H, 26S Proteasome disassembly as a response to mitochondria dysfunction or oxidative stress Cell Reports (in press).