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The Merbl Lab
PTM Profiling: revealing a novel dimension in molecular and clinical diagnosis
With a motivation to decode the regulatory code of Post-Translational Modifications (PTMs), our lab has developed the PTM profiling approach which allows for high-throughput and sensitive detection of multiple ubiquitin and ubiquitin-like modifiers such as SUMO, FAT10, ISG15 and others, in various cellular systems a well as in clinical samples. We utilize this system to map the PTM landscape in health and disease focusing primarily on cancer and autoimmunity.
Cellular proteostasis in health and disease
Cellular proteolysis is involved in essentially every aspect of cell biology. We are interested in understanding the principles underlying the fine-tuning regulation of proteasome activity, substrate specificity and the dynamic rearrangements of the cellular proteome in cancer and immune regulation.
Using our novel Proteasomal Footprinting approach through a method we have termed Mass Spectrometry analysis of Proteolytic Peptides (MAPP) we can examine proteasome-cleaved peptides in cells, in peptide resolution. Utilizing this system we are now exploring the cellular degradome and resulting proteolytic landscape in numerous human disease ranging from cancer to neurodegeneration and autoimmunity.
Golgi Apparatus-Related Degradation (GARD)
Recently we have discovered that 26S proteasomes are bound to the cytosolic surface of Golgi membranes as well as their potential to constitute a novel checkpoint in the secretory pathway. We are now studying their involvement in regulating Golgi organization and homeostasis. Further, we follow this finding to identify the enzymatic machinery involved in sensing and targeting of substrates to localized-proteasomal degradation at the Golgi. We aim to offer novel therapeutic opportunities in different human pathologies related to Golgi function.
The ubiquitin-like modifier FAT10 in cancer and inflammation
We are studying the role of a poorly-studied ubiquitin-like modifier, called FAT10, in tumor-host interactions. FAT10 is up-regulated under inflammatory conditions and was recently suggested as a novel link between cancer and inflammation. Yet, its role in tumor initiation, progression and metastases remain poorly understood. We aim to elucidate the involvement of FAT10 in cancer, identify novel components of this pathway and develop new therapeutic opportunities by inhibiting FAt10 in inflammatory circumstances.
Ubiquitin E3 ligases in cancer and immune regulation
The immune system is a uniquely attractive model system to study mechanisms of PTM control; its complexity, plasticity and the rapid nature of its responses, makes this system highly amenable to PTM regulation. Understanding how the diverse set of signals, that are received by the immune system, are translated into specific activities via control of PTMs should yield new insight into immune regulation and reveal novel targets for therapeutic intervention. Using immunological and molecular tools, we study the signaling dynamics of the ubiquitin system in innate and adaptive immunity.
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