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Ubiquitin signaling networks 1. Ub signaling downstream of cytokine receptors. From Popovic et al. However, important questions remain to be answered. We are also extending our understanding of linear Ub chain involvement in other pathways such as pathogen infection or in cancer pathology.
Moreover, after having generated Ub sensors that can detect linear ubiquitination events following Salmonella infection van Wijk et al. Also genetic studies about cell type specific role in linear ubiquitination as well as the involvement of linear ubiquitination in Salmonella infection are underway Fiskin et al.
Lately, the post-transcriptional regulation of ubiquitin itself has also brought a new level of complexity in signaling regulation by ubiquitin Herhaus and Dikic, Indeed, the phosphorylation of Serine65 of ubiquitin by PINK1 PTEN-induced putative kinase 1 has been shown to regulate the degradation of damaged mitochondria by autophagy mitophagy Kane et al.
PINK1 accumulates at the outer membrane of damaged mitochondria and phosphorylates PARKIN, recruiting it to ubiquitinate mitochondrial membrane proteins and to induce mitophagy.
There is now evidence that PINK1 also directly phosphorylates Ser65 of ubiquitin conjugated to mitochondrial proteins, which facilitates the PARKIN-dependent ubiquitination of mitochondrial substrates potentially by activating PARKIN but also by recruiting it and serving as a localization anchor point on damaged mitochondria Figure 2.
Role of ubiquitin phosphorylation at Ser65 in mitophagy. From Stolz and Dikic, Altogether this indicates that modification of ubiquitin itself by phosphorylation contributes to the regulation of Ub-dependent functions.
In future studies we aim to understand the interplay between phosphorylation of Ub receptors and Ub itself by University of london dissertation binding and structural methods. In addition, other phosphorylation sites in Ub have been reported and their role remain to be determined.
We are particularly interested in understanding the implication of Ub phosphorylation but also in identifying kinases and phosphatases regulating Ub modifications. Among a newly studied UBZ-containing protein was also C1ORF, whose homozygous frame-shift mutation was detected in a patient affected by segmental progeria with chromosomal instability and early-onset hepatocellular carcinoma.
DPCs, if not resolved, become physical impediments to important processes such as DNA replication and gene transcription.
Ubiquitinome during bacterial infection Ubiquitinome during bacterial infection Food- and waterborne bacterial pathogens are a global burden and a major cause of death. At the same time, bacterial resistance to standard antibiotic treatment has evolved into a serious threat worldwide.
Accumulated evidence indicates that deciphering pathogenic and host defense mechanisms during bacterial infections may be the key to future developments of novel antibacterial strategies.
Being one of the most versatile and prevalent post-translational modifications in eukaryotic cells, ubiquitination is also a major regulator of host-pathogen interactions. As such, ubiquitin Ub drives innate immune receptor signaling as well as microbicidal programs including selective autophay of intracellular pathogens Gomes and Dikic, Although prokaryotes do not possess genes encoding for Ub and also lack the Ub-proteasome system, a wide range of bacterial pathogens acquired strategies to exploit the host Ub machinery, particularly E3 ligases, to support their own life cycle, counteract host inflammatory signaling and immune defense programs.
These bacterially encoded E3 ligases can hijack host E2-Ub conjugates and use their intrinsic catalytic activity to modify specific host targets, triggering diverse cellular responses Maculins et al.
However, the substrates of ubiquitination surrounding Salmonella remain poorly understood. Using our established quantitative diGly proteomics platform, we recently recorded the first global ubiquitinome of host epithelial cells infected with Salmonella Typhimurium Fiskin et al, a.
While observed changes in the host ubiquitinome prominently featured components of the actin cytoskeleton and NF-kB pathways, the bacterial ubiquitinome exhibited extensive ubiquitination of various outer membrane proteins possibly being involved in autophagic targeting.
Moreover, we uncovered that Salmonella-derived E3 ligases and deubiquitinases DUBs target a unique subset of host proteins, affecting different stages of Salmonella infection.
Our latest data reveals unique pathogenic mechanisms associated with selected bacterial E3 ligases. Equipped with an ultra-high-pressure-liquid chromatography coupled Orbitrap Q Exactive HF setup, we are currently employing quantitative proteomics of post-translational modifications in various cell types upon bacterial insult to study pathogenesis with a particular focus on secreted bacterial virulence factors, especially bacterial ligases.
A Investigation of the ubiquitinome of Salmonella-infected epithelial cells using diGly and Ub chain-specific proteomics at early 0.
Novel chemistry of ubiquitination Novel chemistry of ubiquitination Although bacteria do not possess the conventional ubiquitin system, several pathogenic bacteria have evolved to meddle with the host ubiquitin system for their advantage Maculins et al. We have identified a hitherto unknown phosphodiesterase PDE domain in SdeA and uncovered the detailed mechanism of ubiquitination by SdeA.
Phosphodiesterase PDE domain of SdeA then catalyzes the hydrolysis of the pyrophosphate bond in the ADP ribose group attached to ubiquitin resulting in the release of AMP and attachment of ubiquitin to substrate serines via a phosphoribose bridge.
We also found that SdeA phosphoribosylates the complete endogenous ubiquitin pool in cells figure 1. Phosphoribosylated ubiquitin is incapable of being a substrate to cellular E1, E2 enzymes and thus severely inhibits conventional ubiquitination and ubiquitin-dependent processes.
This mode of ubiquitinating substrates and modifying ubiquitin was not previously observed and therefore raises an exciting question of diverse biological roles associated to this novel ubiquitin modification. Our future research is aimed at identifying diverse roles of phosphoribosyl-linked serine ubiquitination in mammalian cells.Course Summary.
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