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Biochemistry. Biokhimiia Sep 2022Toll-like receptor 4 (TLR4) is a key pattern recognition receptor that can be activated by bacterial lipopolysaccharide to elicit inflammatory response. Proper...
Toll-like receptor 4 (TLR4) is a key pattern recognition receptor that can be activated by bacterial lipopolysaccharide to elicit inflammatory response. Proper activation of TLR4 is critical for the host defense against microbial infections. Since overactivation of TLR4 causes deleterious effects and inflammatory diseases, its activation needs to be tightly controlled by negative regulatory mechanisms, among which the most pivotal could be deubiquitination of key signaling molecules mediated by deubiquitinating enzymes (DUBs). CYLD is a member of the USP family of DUBs that acts as a critical negative regulator of TLR4-depedent inflammatory responses by deconjugating polyubiquitin chains from signaling molecules, such as TRAF6 and TAK1. Dysregulation of CYLD is implicated in inflammatory diseases. However, how the function of CYLD is regulated during inflammatory response remains largely unclear. Recently, we and other authors have shown that Spata2 functions as an important CYLD partner to regulate enzymatic activity of CYLD and substrate binding by this protein. Here, we show that a Spata2-like protein, Spata2L, can also form a complex with CYLD to inhibit the TLR4-dependent inflammatory response. We found that Spata2L constitutively interacts with CYLD and that the deficiency of Spata2L enhances the LPS-induced NF-κB activation and proinflammatory cytokine gene expression. Mechanistically, Spata2L potentiated CYLD-mediated deubiquitination of TRAF6 and TAK1 likely by promoting CYLD enzymatic activity. These findings identify Spata2L as a novel CYLD regulator, provide new insights into regulatory mechanisms underlying CYLD role in TLR4 signaling, and suggest potential targets for modulating TLR4-induced inflammation.
Topics: Cytokines; Deubiquitinating Enzyme CYLD; Lipopolysaccharides; NF-kappa B; Polyubiquitin; TNF Receptor-Associated Factor 6; Toll-Like Receptor 4
PubMed: 36180997
DOI: 10.1134/S0006297922090085 -
International Journal of Molecular... Nov 2016In the endoplasmic reticulum (ER), misfolded and unfolded proteins are eliminated by a process called ER-associated protein degradation (ERAD) in order to maintain cell...
In the endoplasmic reticulum (ER), misfolded and unfolded proteins are eliminated by a process called ER-associated protein degradation (ERAD) in order to maintain cell homeostasis. In the ERAD pathway, several ER-localized E3 ubiquitin ligases target ERAD substrate proteins for ubiquitination and subsequent proteasomal degradation. However, little is known about how the functions of the ERAD ubiquitin ligases are regulated. Recently, USP19, an ER-anchored deubiquitinating enzyme (DUB), has been suggested to be involved in the regulation of ERAD. In this study, HRD1, an ERAD ubiquitin ligase, is shown to be a novel substrate for USP19. We demonstrate that USP19 rescues HRD1 from proteasomal degradation by deubiquitination of K48-linked ubiquitin chains. In addition, the altered expression of USP19 affects the steady-state levels of HRD1. These results suggest that USP19 regulates the stability of HRD1 and provide insight into the regulatory mechanism of the ERAD ubiquitin ligases.
Topics: Animals; COS Cells; Chlorocebus aethiops; Endopeptidases; Endoplasmic Reticulum; Endoplasmic Reticulum-Associated Degradation; HEK293 Cells; Humans; Proteasome Endopeptidase Complex; Protein Stability; Proteolysis; RNA, Small Interfering; Ubiquitin; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 27827840
DOI: 10.3390/ijms17111829 -
International Journal of Molecular... Aug 2020Deubiquitinating enzymes regulate various cellular processes, particularly protein degradation, localization, and protein-protein interactions. The dysregulation of... (Review)
Review
Deubiquitinating enzymes regulate various cellular processes, particularly protein degradation, localization, and protein-protein interactions. The dysregulation of deubiquitinating enzyme (DUB) activity has been linked to several diseases; however, the function of many DUBs has not been identified. Therefore, the development of methods to assess DUB activity is important to identify novel DUBs, characterize DUB selectivity, and profile dynamic DUB substrates. Here, we review various methods of evaluating DUB activity using cell lysates or purified DUBs, as well as the types of probes used in these methods. In addition, we introduce some techniques that can deliver DUB probes into the cells and cell-permeable activity-based probes to directly visualize and quantify DUB activity in live cells. This review could contribute to the development of DUB inhibitors by providing important information on the characteristics and applications of various probes used to evaluate and detect DUB activity in vitro and in vivo.
Topics: Animals; Deubiquitinating Enzymes; Enzyme Assays; Fluorescence Polarization; Humans; Molecular Probes; Ubiquitin; Ubiquitination
PubMed: 32781716
DOI: 10.3390/ijms21165638 -
Cancer Metastasis Reviews Dec 2017Maintenance of protein homeostasis is a crucial process for the normal functioning of the cell. The regulated degradation of proteins is primarily facilitated by the... (Review)
Review
Maintenance of protein homeostasis is a crucial process for the normal functioning of the cell. The regulated degradation of proteins is primarily facilitated by the ubiquitin proteasome system (UPS), a system of selective tagging of proteins with ubiquitin followed by proteasome-mediated proteolysis. The UPS is highly dynamic consisting of both ubiquitination and deubiquitination steps that modulate protein stabilization and degradation. Deregulation of protein stability is a common feature in the development and progression of numerous cancer types. Simultaneously, the elevated protein synthesis rate of cancer cells and consequential accumulation of misfolded proteins drives UPS addiction, thus sensitizing them to UPS inhibitors. This sensitivity along with the potential of stabilizing pro-apoptotic signaling pathways makes the proteasome an attractive clinical target for the development of novel therapies. Targeting of the catalytic 20S subunit of the proteasome is already a clinically validated strategy in multiple myeloma and other cancers. Spurred on by this success, promising novel inhibitors of the UPS have entered development, targeting the 20S as well as regulatory 19S subunit and inhibitors of deubiquitinating and ubiquitin ligase enzymes. In this review, we outline the manner in which deregulation of the UPS can cause cancer to develop, current clinical application of proteasome inhibitors, and the (pre-)clinical development of novel inhibitors of the UPS.
Topics: Animals; Deubiquitinating Enzymes; Humans; Neoplasms; Proteasome Endopeptidase Complex; Proteasome Inhibitors
PubMed: 29134486
DOI: 10.1007/s10555-017-9697-6 -
The Journal of Biological Chemistry Dec 2003Modification by ubiquitin plays a major role in a broad array of cellular functions. Although reversal of this process, deubiquitination, likely represents an important...
Modification by ubiquitin plays a major role in a broad array of cellular functions. Although reversal of this process, deubiquitination, likely represents an important regulatory step contributing to cellular homeostasis, functions of deubiquitination enzymes still remain poorly characterized. We have previously shown that the ubiquitin protease Ubp3p requires a co-factor, Bre5p, to specifically deubiquitinate the coat protein complex II (COPII) subunit Sec23p, which is involved in anterograde transport between endoplasmic reticulum and Golgi compartments. In the present report, we show that disruption of BRE5 gene also led to a defect in the retrograde transport from the Golgi to the endoplasmic reticulum. Further analysis indicate that the COPI subunit beta'-COP represents another substrate of the Ubp3p.Bre5p complex. All together, our results indicate that the Ubp3p.Bre5p deubiquitination complex co-regulates anterograde and retrograde transports between endoplasmic reticulum and Golgi compartments.
Topics: Amino Acid Sequence; Biological Transport; COP-Coated Vesicles; Endopeptidases; Endoplasmic Reticulum; GTPase-Activating Proteins; Glutathione Transferase; Golgi Apparatus; Molecular Sequence Data; Protein Binding; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Sequence Homology, Amino Acid; Signal Transduction; Temperature; Two-Hybrid System Techniques; Ubiquitin; Ubiquitin Thiolesterase
PubMed: 14593109
DOI: 10.1074/jbc.C300451200 -
Cells Apr 2023OTUD5 (OTU Deubiquitinase 5) is a functional cysteine protease with deubiquitinase activity and is a member of the ovarian tumor protease (OTU) family. OTUD5 is involved... (Review)
Review
OTUD5 (OTU Deubiquitinase 5) is a functional cysteine protease with deubiquitinase activity and is a member of the ovarian tumor protease (OTU) family. OTUD5 is involved in the deubiquitination of many key proteins in various cellular signaling pathways and plays an important role in maintaining normal human development and physiological functions. Its dysfunction can affect physiological processes, such as immunity and DNA damage repair, and it can even lead to tumors, inflammatory diseases and genetic disorders. Therefore, the regulation of OTUD5 activity and expression has become a hot topic of research. A comprehensive understanding of the regulatory mechanisms of OTUD5 and its use as a therapeutic target for diseases is of great value. Herein, we review the physiological processes and molecular mechanisms of OTUD5 regulation, outline the specific regulatory processes of OTUD5 activity and expression, and link OTUD5 to diseases from the perspective of studies on signaling pathways, molecular interactions, DNA damage repair and immune regulation, thus providing a theoretical basis for future studies.
Topics: Female; Humans; Ubiquitination; DNA Repair; Signal Transduction; Ovarian Neoplasms; Deubiquitinating Enzymes
PubMed: 37190070
DOI: 10.3390/cells12081161 -
Cells Mar 2023Ubiquitin-specific peptidase 16 (USP16) is a deubiquitinase that plays a role in the regulation of gene expression, cell cycle progression, and various other functions.... (Review)
Review
Ubiquitin-specific peptidase 16 (USP16) is a deubiquitinase that plays a role in the regulation of gene expression, cell cycle progression, and various other functions. It was originally identified as the major deubiquitinase for histone H2A and has since been found to deubiquitinate a range of other substrates, including proteins from both the cytoplasm and nucleus. USP16 is phosphorylated when cells enter mitosis and dephosphorylated during the metaphase/anaphase transition. While much of USP16 is localized in the cytoplasm, separating the enzyme from its substrates is considered an important regulatory mechanism. Some of the functions that USP16 has been linked to include DNA damage repair, immune disease, tumorigenesis, protein synthesis, coronary artery health, and male infertility. The strong connection to immune response and the fact that multiple oncogene products are substrates of USP16 suggests that USP16 may be a potential therapeutic target for the treatment of certain human diseases.
Topics: Humans; Male; Histones; Mitosis; DNA Repair; Ubiquitin-Specific Proteases; Deubiquitinating Enzymes
PubMed: 36980227
DOI: 10.3390/cells12060886 -
Oncotarget 2015Carcinogenesis is a complex process tightly regulated at multiple levels by post-translational modifications. Epigenetics plays a major role in cancer development, all... (Review)
Review
Carcinogenesis is a complex process tightly regulated at multiple levels by post-translational modifications. Epigenetics plays a major role in cancer development, all stable changes to the gene expression process that are not a result of a direct change in the DNA code are described as epigenetics. Epigenetic processes are regulated by post-translational modifications including ubiquitination which can directly affect either histones or transcription factors or may target their co-factors and interacting partners exerting an indirect effect. Deubiquitination of these target proteins is equally important and alterations in this pathway can also lead to cancer development, progression and metastasis. Only the correct, unaltered balance between ubiquitination and deubiquitination ensures healthy cellular homeostasis. In this review we focus on the role of deubiquitinating (DUB) enzymes in various aspects of epigenetics including the regulation of transcription factors, histone modifications, DNA damage repair pathways and cell cycle regulation. We discuss the impact of those processes on tumourigenesis and potential therapeutic applications of DUBs for cancer treatment.
Topics: Animals; Cell Cycle; Chromatin; DNA; DNA Damage; DNA Repair; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Histones; Humans; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms; Nuclear Proteins; Protein Binding; Protein Processing, Post-Translational; Transcription Factors; Ubiquitin Thiolesterase; Ubiquitin-Specific Peptidase 7; Ubiquitin-Specific Proteases; Ubiquitination
PubMed: 25962961
DOI: 10.18632/oncotarget.3922 -
microRNA-362-3p targets USP22 to retard retinoblastoma growth via reducing deubiquitination of LSD1.Cell Cycle (Georgetown, Tex.) Feb 2021Accumulating evidence has reported the role of microRNA (miR) in retinoblastoma (RB). Therefore, the objective was to discuss how miR-362-3p exerted its function in RB...
Accumulating evidence has reported the role of microRNA (miR) in retinoblastoma (RB). Therefore, the objective was to discuss how miR-362-3p exerted its function in RB cell progression via regulating ubiquitin-specific protease 2 (USP22) and lysine-specific histone demethylase 1 (LSD1). MiR-362-3p, USP22 and LSD1 expression in RB cells and tissues were tested. The biological functions of RB cells were detected via over-expressing miR-362-3p and down-regulating USP22. The target relationship of USP22 and miR-362-3p as well as the interaction of USP22 and LSD1 in RB was verified. Down-regulated miR-362-3p and up-regulated USP22 and LSD1 were demonstrated in RB tissues and cells. Restoring miR-362-3p and depleting USP22 attenuated invasion, proliferation and migration, and facilitated apoptosis of RB cells. USP22 was a target gene of miR-362-3p. USP22 deubiquitinated LSD1 in RB. It is revealed that miR-362-3p targets USP22 and then restrains invasion, proliferation and migration while promotes apoptosis of RB via reducing LSD1 modified by deubiquitination.
Topics: Cell Line, Tumor; Cell Proliferation; Gene Targeting; Histone Demethylases; Humans; MicroRNAs; Retinal Neoplasms; Retinoblastoma; Ubiquitin Thiolesterase; Ubiquitination
PubMed: 33475455
DOI: 10.1080/15384101.2021.1874685 -
Critical Reviews in Oncology/hematology Jul 2016Ubiquitination is the vital system for controlling protein degradation and regulation of basic cellular processes. Deubiquitinases (DUBs) are emerging as an important... (Review)
Review
Ubiquitination is the vital system for controlling protein degradation and regulation of basic cellular processes. Deubiquitinases (DUBs) are emerging as an important regulator of several pathways related to cancer and other diseases. Their ability to detach ubiquitin from the target substrate and regulation of signaling makes it potential target to treat cancer and other fatal diseases. In the current review, we are trying to summarize deubiquitination, and their role in cancer and potential small molecules DUBs inhibitors which can be used as drugs for cancer treatment.
Topics: Deubiquitinating Enzymes; Enzyme Inhibitors; Humans; Immunotherapy; Neoplasms; Ubiquitin; Ubiquitination
PubMed: 27211605
DOI: 10.1016/j.critrevonc.2016.04.018