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Biochimica Et Biophysica Acta. Gene... May 2024Maintenance of genome integrity is a precise but tedious and complex job for the cell. Several post-translational modifications (PTMs) play vital roles in maintaining... (Review)
Review
Maintenance of genome integrity is a precise but tedious and complex job for the cell. Several post-translational modifications (PTMs) play vital roles in maintaining the genome integrity. Although ubiquitination is one of the most crucial PTMs, which regulates the localization and stability of the nonhistone proteins in various cellular and developmental processes, ubiquitination of the histones is a pivotal epigenetic event critically regulating chromatin architecture. In addition to genome integrity, importance of ubiquitination of core histones (H2A, H2A, H3, and H4) and linker histone (H1) have been reported in several cellular processes. However, the complex interplay of histone ubiquitination and other PTMs, as well as the intricate chromatin architecture and dynamics, pose a significant challenge to unravel how histone ubiquitination safeguards genome stability. Therefore, further studies are needed to elucidate the interactions between histone ubiquitination and other PTMs, and their role in preserving genome integrity. Here, we review all types of histone ubiquitinations known till date in maintaining genomic integrity during transcription, replication, cell cycle, and DNA damage response processes. In addition, we have also discussed the role of histone ubiquitination in regulating other histone PTMs emphasizing methylation and acetylation as well as their potential implications in chromatin architecture. Further, we have also discussed the involvement of deubiquitination enzymes (DUBs) in controlling histone ubiquitination in modulating cellular processes.
PubMed: 38763317
DOI: 10.1016/j.bbagrm.2024.195044 -
Autophagy May 2024Macroautophagy/autophagy is essential for the degradation and recycling of cytoplasmic materials. The initiation of this process is determined by...
Macroautophagy/autophagy is essential for the degradation and recycling of cytoplasmic materials. The initiation of this process is determined by phosphatidylinositol-3-kinase (PtdIns3K) complex, which is regulated by factor BECN1 (beclin 1). UFMylation is a novel ubiquitin-like modification that has been demonstrated to modulate several cellular activities. However, the role of UFMylation in regulating autophagy has not been fully elucidated. Here, we found that VCP/p97 is UFMylated on K109 by the E3 UFL1 (UFM1 specific ligase 1) and this modification promotes BECN1 stabilization and assembly of the PtdIns3K complex, suggesting a role for VCP/p97 UFMylation in autophagy initiation. Mechanistically, VCP/p97 UFMylation stabilizes BECN1 through ATXN3 (ataxin 3)-mediated deubiquitination. As a key component of the PtdIns3K complex, stabilized BECN1 facilitates assembly of this complex. Re-expression of VCP/p97, but not the UFMylation-defective mutant, rescued the VCP/p97 depletion-induced increase in MAP1LC3B/LC3B protein expression. We also showed that several pathogenic VCP/p97 mutations identified in a variety of neurological disorders and cancers were associated with reduced UFMylation, thus implicating VCP/p97 UFMylation as a potential therapeutic target for these diseases. : ATG14:autophagy related 14; Baf A:bafilomycin A;CMT2Y: Charcot-Marie-Toothdisease, axonal, 2Y; CYB5R3: cytochromeb5 reductase 3; DDRGK1: DDRGK domain containing 1; DMEM:Dulbecco'smodified Eagle's medium;ER:endoplasmic reticulum; FBS:fetalbovine serum;FTDALS6:frontotemporaldementia and/or amyotrophic lateral sclerosis 6; IBMPFD1:inclusion bodymyopathy with early-onset Paget disease with or withoutfrontotemporal dementia 1; LC-MS/MS:liquid chromatography tandem mass spectrometry; MAP1LC3B/LC3B:microtubule associated protein 1 light chain 3 beta; MS: massspectrometry; NPLOC4: NPL4 homolog, ubiquitin recognition factor;PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3;PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; PtdIns3K:phosphatidylinositol 3-kinase; RPL26: ribosomal protein L26; RPN1:ribophorin I; SQSTM1/p62: sequestosome 1; UBA5: ubiquitin likemodifier activating enzyme 5; UFC1: ubiquitin-fold modifierconjugating enzyme 1; UFD1: ubiquitin recognition factor in ERassociated degradation 1; UFL1: UFM1 specific ligase 1; UFM1:ubiquitin fold modifier 1; UFSP2: UFM1 specific peptidase 2; UVRAG:UV radiation resistance associated; VCP/p97: valosin containingprotein; WT: wild-type.
PubMed: 38762759
DOI: 10.1080/15548627.2024.2356488 -
Biochimica Et Biophysica Acta. Reviews... Jul 2024Tumor recurrence is a mechanism triggered in sparse populations of cancer cells that usually remain in a quiescent state after strict stress and/or therapeutic factors,... (Review)
Review
Tumor recurrence is a mechanism triggered in sparse populations of cancer cells that usually remain in a quiescent state after strict stress and/or therapeutic factors, which is affected by a variety of autocrine and microenvironmental cues. Despite thorough investigations, the biology of dormant and/or cancer stem cells is still not fully elucidated, as for the mechanisms of their reawakening, while only the major molecular patterns driving the relapse process have been identified to date. These molecular patterns profoundly interfere with the elements of cellular proteostasis systems that support the efficiency of the recurrence process. As a major proteostasis machinery, we review the role of the ubiquitin-proteasome system (UPS) in tumor cell dormancy and reawakening, devoting particular attention to the functions of its components, E3 ligases, deubiquitinating enzymes and proteasomes in cancer recurrence. We demonstrate how UPS components functionally or mechanistically interact with the pivotal proteins implicated in the recurrence program and reveal that modulators of the UPS hold promise to become an efficient adjuvant therapy for eradicating refractory tumor cells to impede tumor relapse.
Topics: Humans; Proteasome Endopeptidase Complex; Neoplasms; Ubiquitin; Neoplasm Recurrence, Local; Animals; Ubiquitin-Protein Ligases; Neoplastic Stem Cells; Tumor Microenvironment
PubMed: 38761982
DOI: 10.1016/j.bbcan.2024.189119 -
Biomedicine & Pharmacotherapy =... Jun 2024Ferroptosis is a form of cell death mediated by iron and lipid peroxidation (LPO). Recent studies have provided compelling evidence to support the involvement of... (Review)
Review
Ferroptosis is a form of cell death mediated by iron and lipid peroxidation (LPO). Recent studies have provided compelling evidence to support the involvement of ferroptosis in the pathogenesis of various neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD). Therefore, understanding the mechanisms that regulate ferroptosis in NDDs may improve disease management. Ferroptosis is regulated by multiple mechanisms, and different degradation pathways, including autophagy and the ubiquitinproteasome system (UPS), orchestrate the complex ferroptosis response by directly or indirectly regulating iron accumulation or lipid peroxidation. Ubiquitination plays a crucial role as a protein posttranslational modification in driving ferroptosis. Notably, E3 ubiquitin ligases (E3s) and deubiquitinating enzymes (DUBs) are key enzymes in the ubiquitin system, and their dysregulation is closely linked to the progression of NDDs. A growing body of evidence highlights the role of ubiquitin system enzymes in regulating ferroptosis sensitivity. However, reports on the interaction between ferroptosis and ubiquitin signaling in NDDs are scarce. In this review, we first provide a brief overview of the biological processes and roles of the UPS, summarize the core molecular mechanisms and potential biological functions of ferroptosis, and explore the pathophysiological relevance and therapeutic implications of ferroptosis in NDDs. In addition, reviewing the roles of E3s and DUBs in regulating ferroptosis in NDDs aims to provide new insights and strategies for the treatment of NDDs. These include E3- and DUB-targeted drugs and ferroptosis inhibitors, which can be used to prevent and ameliorate the progression of NDDs.
Topics: Ferroptosis; Humans; Neurodegenerative Diseases; Animals; Ubiquitin-Protein Ligases; Deubiquitinating Enzymes; Ubiquitination; Signal Transduction; Molecular Targeted Therapy
PubMed: 38761423
DOI: 10.1016/j.biopha.2024.116753 -
American Journal of Respiratory Cell... May 2024Lung microvascular endothelial cell (EC) dysfunction is the pathological hallmark of acute respiratory distress syndrome (ARDS). Heat shock protein 90 (HSP90) is a key...
Lung microvascular endothelial cell (EC) dysfunction is the pathological hallmark of acute respiratory distress syndrome (ARDS). Heat shock protein 90 (HSP90) is a key regulator in control of endothelial barrier disruption and inflammation. Our recent study has demonstrated that ubiquitin-specific peptidase 40 (USP40) preserves endothelial integrity by targeting HSP90 for its deubiquitination and inactivation. Indole-3-acetic acid (IAA), a plant hormone of the auxin class, can also be catabolized from dietary tryptophan by the intestinal microbiota. Accumulating evidence suggests that IAA reduces oxidative stress and inflammation, and promotes intestinal barrier function. However, little is known about the role of IAA in endothelial cells and acute lung injury. In this study, we investigated the role of IAA in lung endothelial cell function in the context of acute lung injury. IAA exhibited EC barrier protection against LPS-induced reduction in transendothelial electrical resistance (TEER) and inflammatory responses. The underlying mechanism of IAA on EC protective effects were investigated by examining the influence of IAA on levels of HSP90 ubiquitination and USP40 activity. We identified that IAA, acting as a potential activator of USP40, reduces HSP90 ubiquitination, thereby protecting against LPS-induced inflammation in human lung microvascular endothelial cell (HLMVECs) as well as alleviating experimental lung injury. Furthermore, the EC protective effects of IAA against LPS-induced EC dysfunction and lung injury were abolished in USP40 deficient HLMVECs and lungs of USP40 EC specific knockout (USP40) mice. Taken together, this study reveals that IAA protects against LPS-induced EC dysfunction and lung injury through the activation of USP40.
PubMed: 38761166
DOI: 10.1165/rcmb.2024-0159OC -
Journal of Bone and Mineral Metabolism May 2024Bone homeostasis depends on the regulation of β-catenin in osteoblasts. Glucocorticoids (GCs) are known to diminish β-catenin activity via Wnt pathway signaling,...
Fufang Zhenshu Tiaozhi capsule enhances bone formation and safeguards against glucocorticoid-induced osteoporosis through innovative Mekk2-mediated β-catenin deubiquitination.
INTRODUCTION
Bone homeostasis depends on the regulation of β-catenin in osteoblasts. Glucocorticoids (GCs) are known to diminish β-catenin activity via Wnt pathway signaling, leading to osteoporosis. Conversely, activating β-catenin in osteoblasts through mitogen-activated protein kinase kinase kinase 2 (Mekk2) offers an innovative approach to combat GC-induced osteoporosis (GIOP). Fufang Zhenshu Tiaozhi (FTZ) capsules have shown effectiveness in treating GIOP, but the mechanisms behind this are still unclear.
MATERIALS AND METHODS
In this study, Mekk2 knockout mice (Mekk2) was generated by CRISPR/Cas9. These mice were then subjected to Alcian Blue-Alizarin Red staining and immunofluorescence to assess their bone and cartilage development. To establish models of GIOP, both Mekk2 and wild-type (WT) mice were treated with dexamethasone (DXMS) and subsequently given FTZ capsules. We analyzed the resulting phenotypic changes in these mice using Micro-CT scans and histomorphological studies. Primary osteoblasts, isolated from both Mekk2 and WT mice, underwent qRT-PCR to measure key osteogenesis markers, including Runx2, Sp7, Bgalp, Col1a1 and Alp. Cells were then exposed to treatments with either FTZ or Wnt3a and the phosphorylation levels of β-catenin and Mekk2, along with the protein expression of Runx2, were evaluated using Western blotting and immunoprecipitation. Additionally, C3H10T1/2 cells transfected with TOPflash-luciferase and Renilla luciferase reporters were treated with FTZ and Wnt3a to measure β-catenin activity.
RESULTS
In our study, administering FTZ in vivo effectively prevented bone loss typically induced by GCs. However, it's important to note that this protective effect was substantially reduced in mice lacking Mekk2. Additionally, FTZ showed a significant ability to enhance osteogenic differentiation in primary osteoblasts, doing so by altering the expression of Mekk2. Intriguingly, the impact of FTZ on Mekk2 appears to function through a pathway separate from the traditional Wnt signaling route. Furthermore, our findings indicate that FTZ also promotes the deubiquitination of β-catenin, contributing further to its positive effects on bone health.
CONCLUSIONS
This study suggests that FTZ plays a significant role in protecting bone mass in cases of GIOP. The mechanism through which FTZ confers this benefit involves the activation of Mekk2/β-catenin signaling pathways, which represents a promising alternative strategy to counteract the deleterious effects of GIOP by augmenting osteoblastogenesis.
PubMed: 38755327
DOI: 10.1007/s00774-024-01516-4 -
Brain : a Journal of Neurology May 2024Deubiquitination is critical for the proper functioning of numerous biological pathways such as DNA repair, cell cycle progression, transcription, signal transduction,...
Deubiquitination is critical for the proper functioning of numerous biological pathways such as DNA repair, cell cycle progression, transcription, signal transduction, and autophagy. Accordingly, pathogenic variants in deubiquitinating enzymes (DUBs) have been implicated in neurodevelopmental disorders (ND) and congenital abnormalities. ATXN7L3 is a component of the DUB module of the SAGA complex, and two other related DUB modules, and serves as an obligate adaptor protein of 3 ubiquitin-specific proteases (USP22, USP27X or USP51). Through exome sequencing and GeneMatching, we identified nine individuals with heterozygous variants in ATXN7L3. The core phenotype included global motor and language developmental delay, hypotonia, and distinctive facial characteristics including hypertelorism, epicanthal folds, blepharoptosis, a small nose and mouth, and low-set posteriorly rotated ears. In order to assess pathogenicity, we investigated the effects of a recurrent nonsense variant [c.340C>T; p.(Arg114Ter)] in fibroblasts of an affected individual. ATXN7L3 protein levels were reduced, and deubiquitylation was impaired, as indicated by an increase in histone H2Bub1 levels. This is consistent with the previous observation of increased H2Bub1 levels in Atxn7l3-null mouse embryos, which have developmental delay and embryonic lethality. In conclusion, we present clinical information and biochemical characterization supporting ATXN7L3 variants in the pathogenesis of a rare syndromic ND.
PubMed: 38753057
DOI: 10.1093/brain/awae160 -
Biochimica Et Biophysica Acta. Gene... May 2024A dynamic array of histone post-translational modifications (PTMs) regulate diverse cellular processes in the eukaryotic chromatin. Among them, histone ubiquitination is... (Review)
Review
A dynamic array of histone post-translational modifications (PTMs) regulate diverse cellular processes in the eukaryotic chromatin. Among them, histone ubiquitination is particularly complex as it alters nucleosome surface area fostering intricate cross-talk with other chromatin modifications. Ubiquitin signaling profoundly impacts DNA replication, repair, and transcription. Histones can undergo varied extent of ubiquitination such as mono, multi-mono, and polyubiquitination, which brings about distinct cellular fates. Mechanistic studies of the ubiquitin landscape in chromatin have unveiled a fascinating tapestry of events that orchestrate gene regulation. In this review, we summarize the key contributors involved in mediating different histone ubiquitination and deubiquitination events, and discuss their mechanism which impacts cell transcriptional identity and DNA damage response. We also focus on the proteins bearing epigenetic reader modules critical in discerning site-specific histone ubiquitination, pivotal for establishing complex epigenetic crosstalk. Moreover, we highlight the role of histone ubiquitination in different human diseases including neurodevelopmental disorders and cancer. Overall the review elucidates the intricate orchestration of histone ubiquitination impacting diverse cellular functions and disease pathogenesis, and provides insights into the current challenges of targeting them for therapeutic interventions.
PubMed: 38750882
DOI: 10.1016/j.bbagrm.2024.195033 -
Plant Science : An International... Aug 2024Ubiquitination is a pivotal type of post-translational modification, which plays a far-reaching role in plant growth and development, as well as in the response of...
The de-ubiquitinase UBQUITIN SPECIFIC PROTEASE 15 (UBP15) interacts with the SCF E3 complex adaptor ARABIDOPSIS SKP1 HOMOLOGUE 1 (ASK1) to regulate petal size and fertility in Arabidopsis thaliana.
Ubiquitination is a pivotal type of post-translational modification, which plays a far-reaching role in plant growth and development, as well as in the response of plants to stress. Just like the two sides of a coin, de-ubiquitination also plays an important role in plant life, which has been gradually discovered in recent years. Here, we demonstrate that the UBQUITIN SPECIFIC PROTEASE 15 (UBP15), which is a UBP-type de-ubiquitinase, interacts with the SCF E3 complex adaptor ARABIDOPSIS SKP1 HOMOLOGUE 1 (ASK1) and influences its protein stability to regulate plant fertility and petal size. The UBP15 is associated with the ASK1 physically, as verified by yeast-two-hybrid (Y2H) and protein pull-down in vitro assays. Disruption of ASK1 by a T-DNA insertion generates some abnormal phenotypes, such as low fertility and small petals. Genetic analysis shows that the UBP15 mutation enhances the low-fertility and small-petal phenotypes of ask1 mutant plants. By proteomic analysis, many types of proteins were identified as potential candidate downstream genes associated with the phenotypes of ubp15 ask1 double mutant plants. Taken together, these findings reveal a molecular relationship between ASK1 and UBP15 and their interaction in the regulation of petal size and fertility, which would benefit in-depth research about the ubiquitin-related pathway in plant physiological processes in the future.
Topics: Arabidopsis; Arabidopsis Proteins; Fertility; Flowers; Gene Expression Regulation, Plant
PubMed: 38750799
DOI: 10.1016/j.plantsci.2024.112112 -
BMC Plant Biology May 2024Ubiquitin-specific proteases (UBPs) are a large family of deubiquitinating enzymes (DUBs). They are widespread in plants and are critical for plant growth, development,...
BACKGROUND
Ubiquitin-specific proteases (UBPs) are a large family of deubiquitinating enzymes (DUBs). They are widespread in plants and are critical for plant growth, development, and response to external stresses. However, there are few studies on the functional characteristics of the UBP gene family in the important staple crop, maize (Zea mays L.).
RESULTS
In this study, we performed a bioinformatic analysis of the entire maize genome and identified 45 UBP genes. Phylogenetic analysis indicated that 45 ZmUBP genes can be divided into 15 subfamilies. Analysis of evolutionary patterns and divergence levels indicated that ZmUBP genes were present before the isolation of dicotyledons, were highly conserved and subjected to purifying selection during evolution. Most ZmUBP genes exhibited different expression levels in different tissues and developmental stages. Based on transcriptome data and promoter element analysis, we selected eight ZmUBP genes whose promoters contained a large number of plant hormones and stress response elements and were up-regulated under different abiotic stresses for RT-qPCR analysis, results showed that these genes responded to abiotic stresses and phytohormones to varying degrees, indicating that they play important roles in plant growth and stress response.
CONCLUSIONS
In this study, the structure, location and evolutionary relationship of maize UBP gene family members were analyzed for the first time, and the ZmUBP genes that may be involved in stress response and plant growth were identified by combining promoter element analysis, transcriptome data and RT-qPCR analysis. This study informs research on the involvement of maize deubiquitination in stress response.
Topics: Zea mays; Phylogeny; Gene Expression Regulation, Plant; Ubiquitin-Specific Proteases; Multigene Family; Genome, Plant; Plant Proteins; Stress, Physiological; Genes, Plant; Gene Expression Profiling; Promoter Regions, Genetic
PubMed: 38750451
DOI: 10.1186/s12870-024-04953-5