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Ivan Dikic

Goethe University Frankfurt, Germany

Ivan explores molecular mechanisms of cellular signalling, which have a high relevance to human diseases such as cancer, neurodegenerative disorders and inflammation. Early on, he started to focus on ubiquitin to understand how this modification regulates a large variety of physiological and pathophysiological processes. He established a novel concept of ubiquitin signal recognition by specialized domains serving as ubiquitin receptors. His group demonstrated how multiple monoubiquitination controls EGFR endocytosis and cloned several ubiquitin receptors, which regulate DNA repair, inflammation, cancer, infection and proteasomal degradation. In addition, his team has revealed the functions of linear ubiquitin chains in promoting the NF-kB pathway, thereby impacting on pathogen defenses and other immune responses. Recently, he described the chemistry of a novel type of ubiquitination that is utilized by the bacterial pathogen Legionella to control multiple cellular processes. One of his current major interests lies in selective autophagy, which is essential for the clearance of protein aggregates, pathogens and damaged organelles from the cell. His team has provided important mechanistic insight in the regulatory networks and the structures controlling mitophagy, xenophagy and ER-phagy, shaping host-pathogen interactions and impacting on the development of neurodegenerative diseases like ALS.


Endoplasmic reticulum turnover via selective autophagy

The endoplasmic reticulum (ER) is the largest intracellular endomembrane system enabling synthesis and transport of cellular components. Constant ER turnover is needed to meet different cellular requirements and autophagy plays an important role in this process. In mammalian cells the ER is degraded via a selective autophagy pathway (called ER-phagy), mediated by specific ER-resident proteins that interacts with LC3, via conserved LC3-interacting region (LIR). Reticulon-type protein FAM134B is responsible for the turnover of ER sheets as its overexpression stimulates ER fragmentation and delivery to lysosomes via the autophagy pathway. Conversely, blockade of autophagy or depletion of FAM134B triggers a marked increase in the ER volume. Mutations of FAM134B in humans are unable to act as ER-phagy receptors and cause sensory neurodegeneration. We have recently identified full length reticulon 3 (RTN3) as a specific receptor for the degradation of ER tubules. The major questions we are exploring at the moment deal with the action of reticulone domains in banding the membranes and the regulatory mechanisms of a family of co-receptors that assist FAM134B or RTN3 proteins in selecting the appropriate cargoes during the ER-phagy process. Taken together, ER-phagy possesses the potential to remodel or rebalance the entire ER network and – given the physical and functional connection of ER to other organelles inside the cell – ER-phagy might also impact the function of other organelles as well.