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CBL Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Through its E3 ubiquitin ligase activity, the CBL protein mediates the transfer of ubiquitin from ubiquitin-conjugating enzymes (E2) to specific substrates, and interacts with and promotes tyrosine-phosphorylated substrates for proteasome degradation and ubiquitination. In experimental knockout mice, removal of the CBL gene prolongs activation of tyrosine kinases after cytokine stimulation, enhances sensitivity to hematopoietic growth factors, and expands hematopoietic stem cell pool and myeloproliferative features [16,17].
TDP-43 post-translational modifications in health and disease
Published in Expert Opinion on Therapeutic Targets, 2018
At the protein level, the enzymes responsible for TDP-43 ubiquitination have been initially identified from mass-spec analysis of TDP-43 interactors. Using this approach, it was found that the UBE2E class of ubiquitin-conjugating enzymes was able to promote TDP-43 ubiquitinylation whereas UBPY reduced it [182]. Using a variety of transgenic and lentiviral experimental approaches, another enzyme that has been shown to ubiquitinate TDP-43 is Parkin, an E3 ubiquitin ligase [183]. Ubiquitination of TDP-43 by Parkin facilitates its accumulation in the cytoplasm in a multiprotein complex with HDAC6. Interestingly, TDP-43 expression can increase the levels of Parkin mRNA and protein levels, suggesting the existence of a protective mechanism to remove excess TDP-43 protein from the nucleus [183].
When nature’s robots go rogue: exploring protein homeostasis dysfunction and the implications for understanding human aging disease pathologies
Published in Expert Review of Proteomics, 2018
Julie A. Reisz, Alexander S. Barrett, Travis Nemkov, Kirk C. Hansen, Angelo D’Alessandro
The UPS aids in the homeostasis of short-lived cellular peptides and proteins by tagging damaged proteins with one or more ubiquitin molecules (76 amino acids) at lysine residues, then transporting labeled proteins to the 26S proteasome for degradation. Conjugation of ubiquitin moieties to protein lysines occurs in a step-wise ATP-dependent fashion facilitated by ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2), and ubiquitin-ligating (E3) enzymes. There exist distinct proteasome forms that demonstrate preference for metabolizing mildly oxidized proteins or ubiquitinated proteins [57]. Critically, the ubiquitination process and proteasome function are both ATP dependent. Moreover, oxidation can inhibit ubiquitin-activating enzymes (E1s) and ubiquitin-conjugating enzymes (E2s) via modification (e.g. glutathionylation, nitrosation) of active site cysteine residues along with noted negative impacts on proteasome function [57]. The UPS is critical for homeostasis maintenance in a variety of cell types and helps to preserve cell vitality by degrading proteins of the apoptotic machinery when they are not needed [58]. UPS activity is increased in stem cells (reviewed in [59]), including human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) as a strategy of preserving plasticity. Recently, several E3 ubiquitin ligases were identified as elevated in hESCs compared to differentiated cells as one of the possible mechanisms underlying enhanced UPS [60]. In the event of severe or prolonged cellular stress, the capacity of the UPS to clear ubiquitinated proteins can be exceeded. In such cases, these proteins are directed to autophagy.
Development and characterisation of SMURF2-targeting modifiers
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Dhanoop Manikoth Ayyathan, Gal Levy-Cohen, Moran Shubely, Sandy Boutros-Suleiman, Veronica Lepechkin-Zilbermintz, Michael Shokhen, Amnon Albeck, Arie Gruzman, Michael Blank
Ubiquitin-based protein modification, mediated by the concerted action of ubiquitin-activating factors (E1s), ubiquitin-conjugating enzymes (E2s), and E3 ligases (E3s), controls a plethora of essential molecular and cellular processes both through proteolytic and non-proteolytic mechanisms. These include the regulation of protein turnover and localisation, protein–protein interactions and signal transduction, DNA replication, transcription, damage repair, immune responses, and cell death. Target-oriented E3 ligases provide the specificity to ubiquitin-mediated signalling. It is therefore not surprising that E3s are under intensive investigation as disease biomarkers and drug targets in different pathobiological settings.