חוקר במחלקה לחקר התא ואימונולוגיה בפקולטה למדעי החיים ע"ש ג'ורג' ס. וייז באוניברסיטת תל-אביב
פרופ' ז'ררדו זלמר לדרקרמר
Prof. Lederkremer’s lab has been interested in the mechanisms of protein folding and trafficking in the early secretory pathway of mammalian cells. He has focused especially on mechanisms of ER protein quality control and on recognition and delivery of misfolded proteins from the ER to the cytosolic proteasomes for ERAD. These processes are intimately linked to the genesis of ER stress, which he has also been studying. Specific research topics are:
- Protein misfolding diseases, including neurodegenerative diseases.
- ER stress.
- Mechanisms of endoplasmic reticulum (ER) protein folding and quality control.
- Sugar chain trimming processes as cellular signals for glycoprotein folding status.
- Delivery of misfolded proteins to ER-associated degradation (ERAD).
- Subcellular compartmentalization of ER quality control and ERAD.
His research in these areas has led to some important discoveries. One of them is the identification of a novel subcellular compartment involved in these processes, as a staging ground for ERAD. The second is a process that modifies specifically the sugar chains of misfolded glycoproteins after refolding attempts have failed, creating a signal for delivery to ERAD. He also found that components of the cellular machinery that deliver these misfolded glycoproteins to ERAD have a dual specificity, also for non-glycosylated proteins. These processes are regulated by ER stress and the consequent unfolded protein response (UPR) and he has established that the compartmentalization and assembly of a molecular complex that targets to ERAD are dependent on one of the branches of the UPR. His group has recently found that interference with ERAD and upregulation of the UPR are a main mechanism of cell damage in a neurodegenerative disorder, Huntington’s disease, and that this occurs prior to the appearance of the characteristic large protein inclusions that occur in this disease.
For the complete list, visit his lab website:
Leitman, J., Barak, B., Benyair, R., Shenkman, M., Ashery, U., Hartl, F.U. and Lederkremer, G.Z. ER Stress-induced eIF2-alpha Phosphorylation Underlies Sensitivity of Striatal Neurons to Pathogenic Huntingtin. PLoS One 2014 9(3): e90803. pp. 1-10.
Leitman, J., Shenkman, M., Gofman, Y., Ben-Tal, N., Hendershot, L.M. and Lederkremer, G.Z. Herp coordinates compartmentalization and recruitment of HRD1 and misfolded proteins for ERAD. Mol Biol Cell. 2014 25(7):1050-60.
Leitman, J., Hartl, F.U. and Lederkremer, G.Z. Soluble forms of polyQ-expanded huntingtin rather than large aggregates cause endoplasmic reticulum stress. Nature Commun 2013;4:2753. pp. 1-10.
Shenkman M, Groisman B, Ron E, Avezov E, Hendershot LM, Lederkremer GZ. A shared endoplasmic reticulum-associated degradation pathway involving the EDEM1 protein for glycosylated and nonglycosylated proteins. J Biol Chem. 2013 Jan 25;288(4):2167-78.
Leitman J, Ron E, Ogen-Shtern N, Lederkremer GZ. Compartmentalization of endoplasmic reticulum quality control and ER-associated degradation factors. DNA Cell Biol. 2013 Jan;32(1):2-7. Note: Featured in cover of issue.
Veselkin E, Kondratyev M, Lurie Y, Ron E, Santo M, Reif S, Elashvili I, Bar L, Lederkremer GZ. A secreted form of the asialoglycoprotein receptor, sH2a, as a novel potential noninvasive marker for liver fibrosis. PLoS One. 2011;6(11):e27210.
Benyair R, Ron E, Lederkremer GZ. Protein quality control, retention, and degradation at the endoplasmic reticulum. Int Rev Cell Mol Biol. 2011;292:197-280.
Ron E, Shenkman M, Groisman B, Izenshtein Y, Leitman J, Lederkremer GZ. Bypass of glycan-dependent glycoprotein delivery to ERAD by up-regulated EDEM1. Mol Biol Cell. 2011 Nov;22(21):3945-54. Note: Featured in Mol Biol Cell highlights,
Groisman B, Shenkman M, Ron E, Lederkremer GZ. Mannose trimming is required for delivery of a glycoprotein from EDEM1 to XTP3-B and to late endoplasmic reticulum-associated degradation steps. J Biol Chem. 2011 Jan 14;286(2):1292-300. Note: Featured in Nature Functional Glycomics Gateway.