Detailseite
Projekt
Die Ubiquitinierung als proteolytisches Signal - Neuartige Wege der Modifikation und Erkennung
Antragsteller
Professor Dr. Michael H. Glickman; Professor Dr. Thorsten Hoppe
Fachliche Zuordnung
Zellbiologie
Förderung
Förderung von 2011 bis 2020
Projektkennung
Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 185639753
The "canonical" proteolytic signal that is recognized by the 26S proteasome complex is alysine 48-based polyubiquitin chain. However recent evidence suggests that the proteasome can recognize monoubiquitinated substrates as well as ubiquitin chains with different internallinkages. Furthermore, it appears that even the "canonical" ubiquitination cascade E1-E2-E3explains neither the diversity of the signal in length and linkage type and site, nor therequirements for additional ancillary factors and remodeling. Thus for example, members ofthis consortium found that; (i) monoubiquitination promotes efficient proteasomal processing ofthe p105 NF-KB precursor to the active p50 subunit of the transcriptional activator; (ii) a singleE3 ligase, Hrd1, utilizes three different ubiquitin-conjugating E2 enzymes – Ubc1, 6, and 7, toregulate quality control in the endoplasmic reticulum (ER) via ER-associated degradation(ERAD); (iii) the poly-glutamine expansion of Ataxin 3 which leads to a severe form of ataxia,inactivates its DUB activity suggests that the editing/chain shortening function of the enzymeplays a pathogenetic role in the disease; (iv) monoubiquitination is the predominantmodification identified in the cell. Most surprisingly, perturbing the modifying signal byoverexpression of non-polymerizable ubiquitin did not hamper cellular physiology. Using acombined molecular, biochemical, genetic, cellular, and organismal approach in yeast,nematode, and mammals, we shall map the extent of utilization of these novel signals, their mechanisms of recognition and targeting, and their pathophysiological implications.
DFG-Verfahren
Deutsch-Israelische-Projektkooperationen
Internationaler Bezug
Israel
