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BBB seminar: Terje Johansen

Discovery of receptors for degradation of ubiquitinated targets by autophagy


Terje Johansen
Molecular Cancer Research Group, Institute of Medical Biology, University of Tromsø

The term autophagy (“self-eating”) was coined by Christian de Duve in 1963 to describe a process of lysosomal degradation of cytosolic constituents including organelles like mitochondria. Autophagy can be categorized into several mechanistically distinct forms including macroautophagy, microautophagy and chaperone-mediated autophagy. Macroautophagy (here referred to as autophagy) is the process where a part of the cytosol or an organelle is enwrapped by a double membrane to form an autophagosome followed by fusion of the autophagosome with the lysosome to degrade the contents. The study of autophagy has moved from phenomenology to molecular understanding in less than a decade. The realization that autophagy plays important roles in a host of biological processes and in cancer, neurodegenerative diseases and even life span extension has led to an explosion of interest in the field. Autophagy has generally been thought of as a rather non-specific, bulk degradation pathway that is induced by amino acid starvation. However, recent findings, including contributions from our research group, emphasize that there is some specificity to the process. Additionally, there is a basal, constitutive autophagy that is vital to the cells for them to avoid accumulation of polyubiquitinated protein aggregates and development of degenerative diseases. We have found that the polyubiquitin-binding protein p62/SQSTM1 is degraded by autophagy. p62 is found in cellular inclusion bodies together with polyubiquitinated proteins and in cytosolic protein aggregates that accumulate in various chronic, toxic, and degenerative diseases. We demonstrated that p62 can directly engage a vital component of the autophagic machinery, ATG8 (= LC3 and GABARAP family proteins), to enable degradation of polyubiquitinated protein aggregates by autophagy. As such, p62 constitutes the first described receptor for degradation of ubiquitinated targets by autophagy. Recently, we have discovered that another protein can also act in a similar fashion as p62 to facilitate the autophagic degradation of ubiquitinated cargo. Data from this research will be presented.

Host : Marit Bakke <marit.bakke@biomed.uib.no>, Department of Biomedicine