Novel physiological roles for atypical K11-linked ubiquitin chains

• Applicant: Dr. Anja Bremm
• Subject Area: Biochemistry
• Term: from 2013 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 242840208

Protein ubiquitination is one of the most abundant post-translational modifications (PTMs) in cells. Its versatility arises from the ability of ubiquitin to form eight structurally and functionally distinct polymers, in which ubiquitin molecules are linked via one of seven lysine (K) residues or through the N-terminus. Whereas the roles of K48- and K63-linked ubiquitin chains have been extensively studied during the last decade, cellular functions of the remaining six atypical ubiquitin polymers are less well defined. The main reason why these ubiquitin signals have not been studied is the fact that enzymes for their assembly and disassembly, as well as receptors or substrates of the modifications in cells are largely unknown. The general aim of this proposal is to identify cellular pathways regulated by K11-linked ubiquitin chains, and to understand how this atypical ubiquitin signal is decoded. Starting point for these studies is the K11 linkage-selective deubiquitinase Cezanne. Recently, we observed that Cezanne controls oxygen-independent degradation of the transcription factor HlF-1 via lysosomes. First, we will study Cezanne biology and place emphasis on its role in lysosomal degradation of HIF-1, which is an unexplored control mechanism of this important regulator of cellular oxygen homeostasis. Second, we will use Cezanne as tool to manipulate the content of K11 linkages in cells, and screen for proteins that recognize K11-linked ubiquitin chains, and substrates that are modified with this atypical chain type.

• DFG Programme: Independent Junior Research Groups
• Major Instrumentation: FPLC
• Instrumentation Group: 1350 Flüssigkeits-Chromatographen (außer Aminosäureanalysatoren 317), Ionenaustauscher