The emerging complexity of protein ubiquitination

2009 ◽  
Vol 37 (5) ◽  
pp. 937-953 ◽  
Author(s):  
David Komander
Keyword(s):  
Protein Phosphorylation ◽  
Intracellular Signalling ◽  
Present Review ◽  
Regulatory Mechanisms ◽  
Protein Regulation ◽  
Ubiquitin Chain ◽  
Post Translational Modifications ◽  
Protein Ubiquitination ◽  
Ubiquitin System ◽  
Signalling Cascades

Protein ubiquitination and protein phosphorylation are two fundamental regulatory post-translational modifications controlling intracellular signalling events. However, the ubiquitin system is vastly more complex compared with phosphorylation. This is due to the ability of ubiquitin to form polymers, i.e. ubiquitin chains, of at least eight different linkages. The linkage type of the ubiquitin chain determines whether a modified protein is degraded by the proteasome or serves to attract proteins to initiate signalling cascades or be internalized. The present review focuses on the emerging complexity of the ubiquitin system. I review what is known about individual chain types, and highlight recent advances that explain how the ubiquitin system achieves its intrinsic specificity. There is much to be learnt from the better-studied phosphorylation system, and many key regulatory mechanisms underlying control by protein phosphorylation may be similarly employed within the ubiquitin system. For example, ubiquitination may have important allosteric roles in protein regulation that are currently not appreciated.

scholarly journals Essential role of the linear ubiquitin chain assembly complex and TAK1 kinase in A20 mutant Hodgkin lymphoma

2020 ◽  
Vol 117 (46) ◽  
pp. 28980-28991
Author(s):  
Zhihui Song ◽  
Wei Wei ◽  
Wenming Xiao ◽  
Essel D. Al-Saleem ◽  
Reza Nejati ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Strong Support ◽  
Ubiquitin Chain ◽  
Guide Rna ◽  
Barr Virus ◽  
Protein Ubiquitination ◽  
Crispr Screen ◽  
Epstein Barr

More than 70% of Epstein–Barr virus (EBV)-negative Hodgkin lymphoma (HL) cases display inactivation of TNFAIP3 (A20), a ubiquitin-editing protein that regulates nonproteolytic protein ubiquitination, indicating the significance of protein ubiquitination in HL pathogenesis. However, the precise mechanistic roles of A20 and the ubiquitination system remain largely unknown in this disease. Here, we performed high-throughput CRISPR screening using a ubiquitin regulator-focused single-guide RNA library in HL lines carrying either wild-type or mutant A20. Our CRISPR screening highlights the essential oncogenic role of the linear ubiquitin chain assembly complex (LUBAC) in HL lines, which overlaps with A20 inactivation status. Mechanistically, LUBAC promotes IKK/NF-κB activity and NEMO linear ubiquitination in A20 mutant HL cells, which is required for prosurvival genes and immunosuppressive molecule expression. As a tumor suppressor, A20 directly inhibits IKK activation and HL cell survival via its C-terminal linear-ubiquitin binding ZF7. Clinically, LUBAC activity is consistently elevated in most primary HL cases, and this is correlated with high NF-κB activity and low A20 expression. To further understand the complete mechanism of NF-κB activation in A20 mutant HL, we performed a specifically designed CD83-based NF-κB CRISPR screen which led us to identify TAK1 kinase as a major mediator for NF-κB activation in cells dependent on LUBAC, where the LUBAC-A20 axis regulates TAK1 and IKK complex formation. Finally, TAK1 inhibitor Takinib shows promising activity against HL in vitro and in a xenograft mouse model. Altogether, these findings provide strong support that targeting LUBAC or TAK1 could be attractive therapeutic strategies in A20 mutant HL.

scholarly journals Inherited and Sporadic Amyotrophic Lateral Sclerosis and Fronto-Temporal Lobar Degenerations arising from Pathological Condensates of Phase Separating Proteins

2019 ◽  
Vol 28 (R2) ◽  
pp. R187-R196 ◽  
Author(s):  
Michael Fernandopulle ◽  
GuoZhen Wang ◽  
Jonathon Nixon-Abell ◽  
Seema Qamar ◽  
Varun Balaji ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Recent Work ◽  
Neurodegenerative Disorders ◽  
Low Complexity ◽  
Present Review ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Missense Mutations ◽  
Post Translational Modifications ◽  
Intrinsically Disordered ◽  
Lateral Sclerosis

Abstract Recent work on the biophysics of proteins with low complexity, intrinsically disordered domains that have the capacity to form biological condensates has profoundly altered the concepts about the pathogenesis of inherited and sporadic neurodegenerative disorders associated with pathological accumulation of these proteins. In the present review, we use the FUS, TDP-43 and A11 proteins as examples to illustrate how missense mutations and aberrant post-translational modifications of these proteins cause amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD).

scholarly journals Identification, Characterization, and Regulatory Mechanisms of a Novel EGR1 Splicing Isoform

2019 ◽  
Vol 20 (7) ◽  
pp. 1548 ◽  
Author(s):  
Vincenza Aliperti ◽  
Giulia Sgueglia ◽  
Francesco Aniello ◽  
Emilia Vitale ◽  
Laura Fucci ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cell Types ◽  
Regulatory Mechanisms ◽  
Brain Diseases ◽  
Regulation Of Transcription ◽  
Biological Processes ◽  
Activation Domain ◽  
Post Translational Modifications ◽  
Pathological Conditions ◽  
Proliferation And Apoptosis

EGR1 is a transcription factor expressed in many cell types that regulates genes involved in different biological processes including growth, proliferation, and apoptosis. Dysregulation of EGR1 expression has been associated with many pathological conditions such as tumors and brain diseases. Known molecular mechanisms underlying the control of EGR1 function include regulation of transcription, mRNA and protein stability, and post-translational modifications. Here we describe the identification of a splicing isoform for the human EGR1 gene. The newly identified splicing transcript encodes a shorter protein compared to the canonical EGR1. This isoform lacks a region belonging to the N-terminal activation domain and although it is capable of entering the nucleus, it is unable to activate transcription fully relative to the canonical isoform.

scholarly journals Improved Electrophoretic Separation to Assist the Monitoring of Bcl-xL Post-Translational Modifications

2019 ◽  
Vol 20 (22) ◽  
pp. 5571 ◽  
Author(s):  
Claude Bobo ◽  
Claire Céré ◽  
Mélody Dufossée ◽  
Alain Dautant ◽  
Violaine Moreau ◽  
...  
Keyword(s):  
Alkaline Treatment ◽  
Regulatory Mechanisms ◽  
Electrophoretic Separation ◽  
Survival Functions ◽  
Comprehensive Description ◽  
Post Translational Modifications ◽  
Gel Composition ◽  
Spontaneous Reaction

Bcl-xL is an oncogene of which the survival functions are finely tuned by post-translational modifications (PTM). Within the Bcl-2 family of proteins, Bcl-xL shows unique eligibility to deamidation, a time-related spontaneous reaction. Deamidation is still a largely overlooked PTM due to a lack of easy techniques to monitor Asn→Asp/IsoAsp conversions or Glu→Gln conversions. Being able to detect PTMs is essential to achieve a comprehensive description of all the regulatory mechanisms and functions a protein can carry out. Here, we report a gel composition improving the electrophoretic separation of deamidated forms of Bcl-xL generated either by mutagenesis or by alkaline treatment. Importantly, this new gel formulation proved efficient to provide the long-sought evidence that even doubly-deamidated Bcl-xL remains eligible for regulation by phosphorylation.

Targeting intracellular mediators of pattern-recognition receptor signalling to adjuvant vaccination

2007 ◽  
Vol 35 (6) ◽  
pp. 1501-1503 ◽  
Author(s):  
J. Wales ◽  
E. Andreakos ◽  
M. Feldmann ◽  
B. Foxwell
Keyword(s):  
Immune Response ◽  
Pattern Recognition ◽  
Systemic Toxicity ◽  
Pattern Recognition Receptor ◽  
Intracellular Signalling ◽  
Present Review ◽  
Signalling Molecules ◽  
Receptor Signalling ◽  
Intracellular Mediators ◽  
Recognition Receptor

PRR (pattern-recognition receptor) signalling is involved early in the immune response and therefore would be attractive to target during vaccination. The use of PRR ligands has shown some success; however, toxicity and non-specificity are issues with this strategy. The targeting of PRR intracellular signalling networks would allow for greater specificity and reduced systemic toxicity. The present review examines the successes seen with overexpression or repression of PRR signalling molecules.

scholarly journals Inhibition of Transcription Induces Phosphorylation of YB-1 at Ser102 and Its Accumulation in the Nucleus

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 104 ◽  
Author(s):  
Dmitry A. Kretov ◽  
Daria A. Mordovkina ◽  
Irina A. Eliseeva ◽  
Dmitry N. Lyabin ◽  
Dmitry N. Polyakov ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Polymerase Ii ◽  
Nuclear Localization ◽  
Kinase Activity ◽  
Binding Protein ◽  
Dna Binding Protein ◽  
Regulatory Mechanisms ◽  
Nuclear Accumulation ◽  
Nuclear Retention ◽  
Post Translational Modifications

The Y-box binding protein 1 (YB-1) is an RNA/DNA-binding protein regulating gene expression in the cytoplasm and the nucleus. Although mostly cytoplasmic, YB-1 accumulates in the nucleus under stress conditions. Its nuclear localization is associated with aggressiveness and multidrug resistance of cancer cells, which makes the understanding of the regulatory mechanisms of YB-1 subcellular distribution essential. Here, we report that inhibition of RNA polymerase II (RNAPII) activity results in the nuclear accumulation of YB-1 accompanied by its phosphorylation at Ser102. The inhibition of kinase activity reduces YB-1 phosphorylation and its accumulation in the nucleus. The presence of RNA in the nucleus is shown to be required for the nuclear retention of YB-1. Thus, the subcellular localization of YB-1 depends on its post-translational modifications (PTMs) and intracellular RNA distribution.

MicroRNA in glutamate receptor-dependent neurological diseases

2017 ◽  
Vol 131 (14) ◽  
pp. 1591-1604 ◽  
Author(s):  
Walid A. Alsharafi ◽  
Zhaohui Luo ◽  
Xiaoyan Long ◽  
Yuanyuan Xie ◽  
Bo Xiao
Keyword(s):  
Glutamate Receptor ◽  
Therapeutic Target ◽  
Recent Literature ◽  
Neurological Diseases ◽  
Present Review ◽  
Regulatory Mechanisms ◽  
Promising Therapeutic Target ◽  
Wide Range

Glutamate-mediated excitotoxicity is the major neuropathological process contributing to numerous neurological diseases. Recently, emerging evidence indicates that microRNAs (miRNAs) play essential roles in the pathophysiology of a wide range of neurological diseases. Notably, there have been significant developments in understanding the biogenesis of miRNAs, their regulatory mechanisms, and their potential as effective biomarkers and therapies. In the present review, we summarize the recent literature that highlights the versatile roles played by miRNAs in glutamate receptor (GluR)-dependent neurological diseases. Based on the reported studies to date, modulation of miRNAs could emerge as a promising therapeutic target for a variety of neurological diseases that were discussed in this review.

Domain-Specific Activation of Death-Associated Intracellular Signalling Cascades by the Cellular Prion Protein in Neuroblastoma Cells

2015 ◽  
Vol 53 (7) ◽  
pp. 4438-4448 ◽  
Author(s):  
Silvia Vilches ◽  
Cristina Vergara ◽  
Oriol Nicolás ◽  
Ágata Mata ◽  
José A. del Río ◽  
...  
Keyword(s):  
Prion Protein ◽  
Neuroblastoma Cells ◽  
Cellular Prion Protein ◽  
Intracellular Signalling ◽  
Domain Specific ◽  
Signalling Cascades

scholarly journals Omic-Sig: Utilizing Omics Data to Explore and Visualize Kinase-Substrate Interactions

2019 ◽  
Author(s):  
T. Mamie Lih ◽  
David J. Clark ◽  
Hui Zhang
Keyword(s):  
Protein Phosphorylation ◽  
Software Tool ◽  
Omics Data ◽  
Additional Insight ◽  
Post Translational Modifications ◽  
Kinase Substrate ◽  
Cellular Processes ◽  
Visualization Software ◽  
And Control ◽  
Insight Into

AbstractProtein phosphorylation is one of the most prevalent post-translational modifications, resulting from the activity of protein kinases phosphorylating specific substrates. Multiple cellular processes are regulated via protein phosphorylation, with aberrant signaling driven by dysregulation of phosphorylation events and associating with disease progression (e.g., cancer). Mass spectrometry-based phosphoprotomics approaches can be leveraged for studying alterations of kinase-substrate activity in clinical cohorts. However, the information gained via interrogation of global proteomes and transcriptomes can offer additional insight into the interaction of kinases and their respective substrates. Therefore, we have developed the bioinformatics, data visualization software tool, Omic-Sig, which can stratify prominent phospho-substrates and their associated kinases based on differential abundances between case and control samples (e.g., tumors and their normal adjacent tissues from a cancer cohort) in a multi-omics fashion. Omic-Sig is available at https://github.com/hzhangjhu/Omic-Sig.

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