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Linear ubiquitin chains - novel cellular signals involved in inflammation and cancer

Final Report Summary - LINEUB (Linear ubiquitin chains - novel cellular signals involved in inflammation and cancer)

Ubiquitin was originally discovered as a major regulator of the life cycle of proteins, with the covalent attachment of ubiquitin to target proteins being dubbed as “kiss of death”. As such, ubiquitin acted as a critical quality control signal in the cell. However, ubiquitin has many other functions in the cells and it was soon established that it is the most versatile form of post-translational modification known to date. Ubiquitin can be attached as a single molecule or in chains of several ubiquitin molecules, and depending on the length and architecture of those chains, different signals are relayed. Through the versatility of this system, ubiquitin signals control all major cellular process with far-reaching biomedical implications.
A couple of years ago, linear ubiquitin chains were discovered by Kazu Iwai’s group; however, the role of this novel kind of chains and how they are being recognized and decoded remained a mystery. Therefore, we proposed to address the physiological role of linear ubiquitin chains. Initially, we solved the structure of a linear ubiquitin chain in complex with the ubiquitin-binding domain in NEMO – a challenging task that many labs tried to accomplish at the time (Cell, 2009). This structure and the following functional studies explained the deleterious effects of NEMO gene mutations in patients suffering from X-linked ectodermal dysplasia and immunodeficiency.
We continued to study the ubiquitin ligase involved in making linear ubiquitin chains, its substrates, and the specificity of ubiquitin binding domains that decode linear chains in vivo. We discovered a novel member of the linear ubiquitin ligase complex (LUBAC), SHARPIN, which functions as an adaptor protein. Loss of SHARPIN leads to chronic dermatitis and multi-organ failure in mice and we uncovered a novel-signalling pathway regulating skin inflammation (Nature, 2011). Later, we revealed how activity of LUBAC is fine-tuned by showing that the ligase subunit HOIP and the deubiquitinase OTULIN act together as a bimolecular editing pair (Molecular Cell, 2014). Moreover, we explained the specificity of the NEMO UBAN domain towards linear versus Lys63 branched chains and revealed their contribution for dynamic importance of the NF-KB pathway.
We have also proposed that other receptors like NEMO exist for the recognition and the clearance of protein aggregates, damaged organelles and pathogenic bacteria by the process of autophagy. We showed that optineurin (OPTN, has a UBAN domain like NEMO) functions as an inducible autophagy receptor for clearance of pathogenic Salmonella. This work was a major conceptual breakthrough to unveil that phosphorylation of autophagy receptors may serve as a general inducer to trigger this active process (Science, 2011).
We continued to show that linear ubiquitination affects both membrane trafficking as well as autophagy pathways, and identified PLEKHM1 as an adaptor platform that as common node coordinating the different trafficking arms of the endolysosomal system (Molecular Cell, 2015; Cell Host Microbes, 2015).
Reaching far beyond the original scope of this project, and in collaboration with clinical geneticists, we recently have also linked the OPTN/TBK1 autophagy pathway to the pathogenesis of amyotrophic lateral sclerosis. (Nature Neuroscience, 2015).
Finally, we have created a toolbox with fluorescently-labelled ubiquitin sensors which enables us to track ubiquitin signals in the cells (Nature Protocols, 2013; Molecular Cell, 2012). In addition, we have developed small peptides interfering with linear ubiquitin signalling.