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1.
Blood Cancer Discov ; 5(1): 56-73, 2024 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-37934799

RESUMEN

Immunomodulatory drugs (IMiD) are a backbone therapy for multiple myeloma (MM). Despite their efficacy, most patients develop resistance, and the mechanisms are not fully defined. Here, we show that IMiD responses are directed by IMiD-dependent degradation of IKZF1 and IKZF3 that bind to enhancers necessary to sustain the expression of MYC and other myeloma oncogenes. IMiD treatment universally depleted chromatin-bound IKZF1, but eviction of P300 and BRD4 coactivators only occurred in IMiD-sensitive cells. IKZF1-bound enhancers overlapped other transcription factor binding motifs, including ETV4. Chromatin immunoprecipitation sequencing showed that ETV4 bound to the same enhancers as IKZF1, and ETV4 CRISPR/Cas9-mediated ablation resulted in sensitization of IMiD-resistant MM. ETV4 expression is associated with IMiD resistance in cell lines, poor prognosis in patients, and is upregulated at relapse. These data indicate that ETV4 alleviates IKZF1 and IKZF3 dependency in MM by maintaining oncogenic enhancer activity and identify transcriptional plasticity as a previously unrecognized mechanism of IMiD resistance. SIGNIFICANCE: We show that IKZF1-bound enhancers are critical for IMiD efficacy and that the factor ETV4 can bind the same enhancers and substitute for IKZF1 and mediate IMiD resistance by maintaining MYC and other oncogenes. These data implicate transcription factor redundancy as a previously unrecognized mode of IMiD resistance in MM. See related article by Welsh, Barwick, et al., p. 34. See related commentary by Yun and Cleveland, p. 5. This article is featured in Selected Articles from This Issue, p. 4.


Asunto(s)
Mieloma Múltiple , Humanos , Proteínas que Contienen Bromodominio , Proteínas de Ciclo Celular , Agentes Inmunomoduladores , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Recurrencia Local de Neoplasia , Proteínas Nucleares , Proteínas Proto-Oncogénicas c-ets/genética , Factores de Transcripción/genética , Ubiquitina-Proteína Ligasas/fisiología , Ubiquitina-Proteína Ligasas/uso terapéutico
2.
Front Immunol ; 14: 1202633, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37215134

RESUMEN

Bladder cancer is one of the common malignant urothelial tumors. Post-translational modification (PTMs), including ubiquitination, acetylation, methylation, and phosphorylation, have been revealed to participate in bladder cancer initiation and progression. Ubiquitination is the common PTM, which is conducted by E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzyme and E3 ubiquitin-protein ligase. E3 ubiquitin ligases play a key role in bladder oncogenesis and progression and drug resistance in bladder cancer. Therefore, in this review, we summarize current knowledge regarding the functions of E3 ubiquitin ligases in bladder cancer development. Moreover, we provide the evidence of E3 ubiquitin ligases in regulation of immunotherapy in bladder cancer. Furthermore, we mention the multiple compounds that target E3 ubiquitin ligases to improve the therapy efficacy of bladder cancer. We hope our review can stimulate researchers and clinicians to investigate whether and how targeting E3 ubiquitin ligases acts a novel strategy for bladder cancer therapy.


Asunto(s)
Ubiquitina-Proteína Ligasas , Neoplasias de la Vejiga Urinaria , Humanos , Ubiquitina-Proteína Ligasas/fisiología , Neoplasias de la Vejiga Urinaria/terapia , Ubiquitinas , Inmunoterapia , Enzimas Desubicuitinizantes
3.
Gene ; 814: 146144, 2022 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-34990797

RESUMEN

The function of the HERC1 gene has mainly been delineated by studying Herc1tbl (tambaleante) mutant mice, characterized by losses in cerebellar Purkinje cells, a lower number of synaptic vesicles in the hippocampus, and anomalies in climbing fiber projections from the inferior olive as well as alpha-motoneuron projections to the skeletal muscle. The salient behavioral phenotypes include cerebellar ataxia, a loss in motor coordination, muscle weakness, and spatial deficits. Similar neuropathological and behavioral profiles have been described in childhood-onset subjects with HERC1 variants, including cerebellar ataxia and hypotonia.


Asunto(s)
Ubiquitina-Proteína Ligasas/genética , Animales , Humanos , Ratones , Mutación , Enfermedades del Sistema Nervioso Periférico/genética , Ubiquitina-Proteína Ligasas/fisiología
4.
J Cell Biochem ; 123(2): 161-182, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34520596

RESUMEN

Viruses are known to cause various diseases in human and also infect other species such as animal plants, fungi, and bacteria. Replication of viruses depends upon their interaction with hosts. Human cells are prone to such unwanted viral infections. Disintegration and reconstitution require host machinery and various macromolecules like DNA, RNA, and proteins are invaded by viral particles. E3 ubiquitin ligases are known for their specific function, that is, recognition of their respective substrates for intracellular degradation. Still, we do not understand how ubiquitin proteasome system-based enzymes E3 ubiquitin ligases do their functional interaction with different viruses. Whether E3 ubiquitin ligases help in the elimination of viral components or viruses utilize their molecular capabilities in their intracellular propagation is not clear. The first time our current article comprehends fundamental concepts and new insights on the different viruses and their interaction with various E3 Ubiquitin Ligases. In this review, we highlight the molecular pathomechanism of viruses linked with E3 Ubiquitin Ligases dependent mechanisms. An enhanced understanding of E3 Ubiquitin Ligase-mediated removal of viral proteins may open new therapeutic strategies against viral infections.


Asunto(s)
Ubiquitina-Proteína Ligasas/fisiología , Proteínas Virales/fisiología , Virosis/enzimología , Replicación Viral/fisiología , Transformación Celular Viral/fisiología , Proteínas Cullin/fisiología , Endosomas/virología , Interacciones Huésped-Patógeno , Humanos , Inmunidad Innata , Inflamación/enzimología , Inflamación/virología , Neoplasias/enzimología , Neoplasias/virología , Virus Oncogénicos/fisiología , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis , Proteínas de Motivos Tripartitos/fisiología , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Virosis/inmunología , Virosis/virología , Replicación Viral/efectos de los fármacos , Tratamiento Farmacológico de COVID-19
5.
Gene ; 809: 146028, 2022 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-34687788

RESUMEN

Seven in absentia homolog 2 (Siah2), an RING E3 ubiquitin ligases, has been characterized to play the vital role in tumorigenesis and cancer progression. Numerous studies have determined that Siah2 promotes tumorigenesis in a variety of human malignancies such as prostate, lung, gastric, and liver cancers. However, several studies revealed that Siah2 exhibited tumor suppressor function by promoting the proteasome-mediated degradation of several oncoproteins, suggesting that Siah2 could exert its biological function according to different stages of tumor development. Moreover, Siah2 is subject to complex regulation, especially the phosphorylation of Siah2 by a variety of protein kinases to regulate its stability and activity. In this review, we describe the structure and regulation of Siah2 in human cancer. Moreover, we highlight the critical role of Siah2 in tumorigenesis. Furthermore, we note that the potential clinical applications of targeting Siah2 in cancer therapy.


Asunto(s)
Neoplasias/patología , Neoplasias/terapia , Proteínas Nucleares/fisiología , Ubiquitina-Proteína Ligasas/fisiología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunoterapia/métodos , Masculino , Terapia Molecular Dirigida/métodos , Proteínas Nucleares/química , Ubiquitina-Proteína Ligasas/química
6.
Biomed Pharmacother ; 146: 112585, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34968923

RESUMEN

The balance between ubiquitination and deubiquitination is crucial for protein stability, function and location under physiological conditions. Dysregulation of E1/E2/E3 ligases or deubiquitinases (DUBs) results in malfunction of the ubiquitin system and is involved in many diseases. Increasing reports have indicated that ubiquitin-specific peptidases (USPs) play a part in the progression of many kinds of cancers and could be good targets for anticancer treatment. Glioma is the most common malignant tumor in the central nervous system. Clinical treatment for high-grade glioma is unsatisfactory thus far. Multiple USPs are dysregulated in glioma and have the potential to be therapeutic targets. In this review, we collected studies on the roles of USPs in glioma progression and summarized the mechanisms of USPs in glioma tumorigenesis, malignancy and chemoradiotherapy resistance.


Asunto(s)
Glioma/fisiopatología , Ubiquitina-Proteína Ligasas/fisiología , Proteasas Ubiquitina-Específicas/metabolismo , Ubiquitinación/fisiología , Animales , Autofagia/fisiología , Carcinogénesis/metabolismo , Reparación del ADN/fisiología , Resistencia a Antineoplásicos/fisiología , Humanos , Tolerancia a Radiación/fisiología , Transducción de Señal/fisiología
7.
Cell Mol Life Sci ; 79(1): 47, 2021 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-34921635

RESUMEN

Mahogunin Ring Finger 1 (MGRN1) is an E3-ubiquitin ligase absent in dark-furred mahoganoid mice. We investigated the mechanisms of hyperpigmentation in Mgrn1-null melan-md1 melanocytes, Mgrn1-KO cells obtained by CRISPR-Cas9-mediated knockdown of Mgrn1 in melan-a6 melanocytes, and melan-a6 cells depleted of MGRN1 by siRNA treatment. Mgrn1-deficient melanocytes showed higher melanin content associated with increased melanosome abundance and higher fraction of melanosomes in highly melanized maturation stages III-IV. Expression, post-translational processing and enzymatic activity of the rate-limiting melanogenic enzyme tyrosinase measured in cell-free extracts were comparable in control and MGRN1-depleted cells. However, tyrosinase activity measured in situ in live cells and expression of genes associated with regulation of pH increased upon MGRN1 repression. Using pH-sensitive fluorescent probes, we found that downregulation of MGRN1 expression in melanocytes and melanoma cells increased the pH of acidic organelles, including melanosomes, strongly suggesting a previously unknown role of MGRN1 in the regulation of melanosomal pH. Among the pH regulatory genes upregulated by Mgrn1 knockdown, we identified those encoding several subunits of the vacuolar adenosine triphosphatase V-ATPase (mostly Atp6v0d2) and a calcium channel of the transient receptor potential channel family, Mucolipin 3 (Mcoln3). Manipulation of expression of the Mcoln3 gene showed that overexpression of Mcoln3 played a significant role in neutralization of the pH of acidic organelles and activation of tyrosinase in MGRN1-depleted cells. Therefore, lack of MGRN1 led to cell-autonomous stimulation of pigment production in melanocytes mostly by increasing tyrosinase specific activity through neutralization of the melanosomal pH in a MCOLN3-dependent manner.


Asunto(s)
Pigmentación , Piel/metabolismo , Canales de Potencial de Receptor Transitorio/metabolismo , Ubiquitina-Proteína Ligasas/fisiología , Animales , Humanos , Concentración de Iones de Hidrógeno , Melanocitos , Melanoma Experimental , Melanosomas , Ratones , Piel/citología , Piel/patología
8.
Int J Mol Sci ; 22(21)2021 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-34768802

RESUMEN

Cardiac development is a complex process that is strictly controlled by various factors, including PcG protein complexes. Several studies have reported the critical role of PRC2 in cardiogenesis. However, little is known about the regulation mechanism of PRC1 in embryonic heart development. To gain more insight into the mechanistic role of PRC1 in cardiogenesis, we generated a PRC1 loss-of-function zebrafish line by using the CRISPR/Cas9 system targeting rnf2, a gene encoding the core subunit shared by all PRC1 subfamilies. Our results revealed that Rnf2 is not involved in cardiomyocyte differentiation and heart tube formation, but that it is crucial to maintaining regular cardiac contraction. Further analysis suggested that Rnf2 loss-of-function disrupted cardiac sarcomere assembly through the ectopic activation of non-cardiac sarcomere genes in the developing heart. Meanwhile, Rnf2 deficiency disrupts the construction of the atrioventricular canal and the sinoatrial node by modulating the expression of bmp4 and other atrioventricular canal marker genes, leading to an impaired cardiac conduction system. The disorganized cardiac sarcomere and defective cardiac conduction system together contribute to defective cardiac contraction. Our results emphasize the critical role of PRC1 in the cardiac development.


Asunto(s)
Corazón/crecimiento & desarrollo , Contracción Muscular , Miocardio/metabolismo , Sarcómeros/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas de Pez Cebra/metabolismo , Pez Cebra/metabolismo , Animales , Animales Modificados Genéticamente , Desarrollo Embrionario , Corazón/fisiología , Mutación con Pérdida de Función , Complejo Represivo Polycomb 1/metabolismo , Complejo Represivo Polycomb 1/fisiología , Sarcómeros/fisiología , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/fisiología , Pez Cebra/fisiología , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/fisiología
9.
PLoS One ; 16(11): e0260072, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34797853

RESUMEN

Neurodevelopmental disorders such as epilepsy and autism have been linked to an imbalance of excitation and inhibition (E/I) in the central nervous system. The simplicity and tractability of C. elegans allows our electroconvulsive seizure (ES) assay to be used as a behavioral readout of the locomotor circuit and neuronal function. C. elegans possess conserved nervous system features such as gamma-aminobutyric acid (GABA) and GABA receptors in inhibitory neurotransmission, and acetylcholine (Ach) and acetylcholine receptors in excitatory neurotransmission. Our previously published data has shown that decreasing inhibition in the motor circuit, via GABAergic manipulation, will extend the time of locomotor recovery following electroshock. Similarly, mutations in a HECT E3 ubiquitin ligase called EEL-1 leads to impaired GABAergic transmission, E/I imbalance and altered sensitivity to electroshock. Mutations in the human ortholog of EEL-1, called HUWE1, are associated with both syndromic and non-syndromic intellectual disability. Both EEL-1 and its previously established binding protein, OGT-1, are expressed in GABAergic motor neurons, localize to GABAergic presynaptic terminals, and function in parallel to regulate GABA neuron function. In this study, we tested behavioral responses to electroshock in wildtype, ogt-1, eel-1 and ogt-1; eel-1 double mutants. Both ogt-1 and eel-1 null mutants have decreased inhibitory GABAergic neuron function and increased electroshock sensitivity. Consistent with EEL-1 and OGT-1 functioning in parallel pathways, ogt-1; eel-1 double mutants showed enhanced electroshock susceptibility. Expression of OGT-1 in the C. elegans nervous system rescued enhanced electroshock defects in ogt-1; eel-1 double mutants. Application of a GABA agonist, Baclofen, decreased electroshock susceptibility in all animals. Our C. elegans electroconvulsive seizure assay was the first to model a human X-linked Intellectual Disability (XLID) associated with epilepsy and suggests a potential novel role for the OGT-1/EEL-1 complex in seizure susceptibility.


Asunto(s)
Proteínas de Caenorhabditis elegans/metabolismo , N-Acetilglucosaminiltransferasas/metabolismo , Convulsiones/genética , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/fisiología , Susceptibilidad a Enfermedades/metabolismo , Neuronas GABAérgicas/metabolismo , Genes Ligados a X/genética , Predisposición Genética a la Enfermedad/genética , Discapacidad Intelectual/genética , N-Acetilglucosaminiltransferasas/fisiología , Sistema Nervioso/metabolismo , Fenómenos Fisiológicos del Sistema Nervioso , Terminales Presinápticos/metabolismo , Convulsiones/metabolismo , Transmisión Sináptica , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/fisiología , Ácido gamma-Aminobutírico/metabolismo
10.
Sci Rep ; 11(1): 19414, 2021 09 30.
Artículo en Inglés | MEDLINE | ID: mdl-34593829

RESUMEN

In humans, loss-of-function mutations in the UBE3A gene lead to the neurodevelopmental disorder Angelman syndrome (AS). AS patients have severe impairments in speech, learning and memory, and motor coordination, for which there is currently no treatment. In addition, UBE3A is duplicated in > 1-2% of patients with autism spectrum disorders-a further indication of the significant role it plays in brain development. Altered expression of UBE3A, an E3 ubiquitin ligase, is hypothesized to lead to impaired levels of its target proteins, but identifying the contribution of individual UBE3A targets to UBE3A-dependent deficits remains of critical importance. Ephexin5 is a putative UBE3A substrate that has restricted expression early in development, regulates synapse formation during hippocampal development, and is abnormally elevated in AS mice, modeled by maternally-derived Ube3a gene deletion. Here, we report that Ephexin5 can be directly ubiquitylated by UBE3A. Furthermore, removing Ephexin5 from AS mice specifically rescued hippocampus-dependent behaviors, CA1 physiology, and deficits in dendritic spine number. Our findings identify Ephexin5 as a key driver of hippocampal dysfunction and related behavioral deficits in AS mouse models. These results demonstrate the exciting potential of targeting Ephexin5, and possibly other UBE3A substrates, to improve symptoms of AS and other UBE3A-related developmental disorders.


Asunto(s)
Síndrome de Angelman/metabolismo , Hipocampo , Aprendizaje , Ubiquitina-Proteína Ligasas/fisiología , Animales , Células Cultivadas , Femenino , Hipocampo/metabolismo , Hipocampo/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas
11.
Nucleic Acids Res ; 49(18): 10507-10523, 2021 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-34534348

RESUMEN

A DNA replication program, which ensures that the genome is accurately and wholly replicated, is established during G1, before the onset of S phase. In G1, replication origins are licensed, and upon S phase entry, a subset of these will form active replisomes. Tight regulation of the number of active replisomes is crucial to prevent replication stress-induced DNA damage. TICRR/TRESLIN is essential for DNA replication initiation, and the level of TICRR and its phosphorylation determine the number of origins that initiate during S phase. However, the mechanisms regulating TICRR protein levels are unknown. Therefore, we set out to define the TICRR/TRESLIN protein dynamics throughout the cell cycle. Here, we show that TICRR levels are high during G1 and dramatically decrease as cells enter S phase and begin DNA replication. We show that degradation of TICRR occurs specifically during S phase and depends on ubiquitin ligases and proteasomal degradation. Using two targeted siRNA screens, we identify CRL4DTL as a cullin complex necessary for TICRR degradation. We propose that this mechanism moderates the level of TICRR protein available for replication initiation, ensuring the proper number of active origins as cells progress through S phase.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Fase S , Ubiquitina-Proteína Ligasas/metabolismo , Proteína Quinasa CDC2/antagonistas & inhibidores , Proteínas Portadoras/fisiología , Ciclo Celular , Proteínas de Ciclo Celular/fisiología , Línea Celular Tumoral , Proteínas Cullin/metabolismo , Proteínas Cullin/fisiología , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Proteínas de Unión al ADN/fisiología , Humanos , Antígeno Nuclear de Célula en Proliferación/fisiología , Ubiquitina-Proteína Ligasas/fisiología
12.
Carcinogenesis ; 42(10): 1223-1231, 2021 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-34546340

RESUMEN

Bortezomib-based chemotherapy represents the most prevalent regimens for multiple myeloma (MM), whereas acquired drug resistance remains a major obstacle. Myeloma cells often produce excessive amount of dickkopf-1 (DKK1), giving rise to myeloma bone disease. However, it remains obscure about the effects and mechanisms of DKK1 in the progression and bortezomib responsiveness of MM cells. In the current study, we found WWP2, an E3 ubiquitin-protein ligase, was downregulated in the bortezomib-resistant cells along with high expression of DKK1. Further investigation revealed that WWP2 was a direct target of Wnt/ß-catenin signaling pathway, and DKK1 suppressed the expression of WWP2 via canonical Wnt signaling. We further identified that WWP2 mediated the ubiquitination and degradation of GLI2, a main transcriptional factor of the Hedgehog (Hh) pathway. Therefore, DKK1-induced WWP2 downregulation improved GLI2 stability and activation of Hh signaling pathway, contributing to the resistance to bortezomib of MM cells. Clinical data also validated that WWP2 expression was associated with the treatment response and clinic outcomes of MM patients. WWP2 overexpression restricted MM progression and enhanced cell sensitivity to bortezomib treatment in vitro and in vivo. Taken together, our findings demonstrate that DKK1 facilitates the generation of bortezomib resistance in MM via downregulating WWP2 and activating Hh pathway. Thus, the manipulation of DKK1-WWP2-GLI2 axis might sensitize myeloma cells to proteasome inhibitors.


Asunto(s)
Antineoplásicos/uso terapéutico , Bortezomib/uso terapéutico , Resistencia a Antineoplásicos/fisiología , Péptidos y Proteínas de Señalización Intercelular/fisiología , Mieloma Múltiple/tratamiento farmacológico , Proteínas Nucleares/metabolismo , Ubiquitina-Proteína Ligasas/genética , Proteína Gli2 con Dedos de Zinc/metabolismo , Línea Celular Tumoral , Células HEK293 , Humanos , Mieloma Múltiple/metabolismo , Resultado del Tratamiento , Ubiquitina-Proteína Ligasas/fisiología , Ubiquitinación , Vía de Señalización Wnt
13.
Autophagy ; 17(11): 3884-3886, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34486484

RESUMEN

Among other mechanisms, mitochondrial membrane dynamics including mitochondrial fission and fusion, and the activity of the ubiquitin (Ub)-proteasome system (UPS) both are critical for maintaining mitochondrial function. To advance our knowledge of the role of mitochondrial fission, the UPS, and how they coordinatively affect mitochondrial response to proteotoxicity, we analyzed mitochondrial ubiquitination and mitochondria-specific autophagy (mitophagy) in E3 Ub ligase PRKN/parkin-expressing and -deficient cells. Through imaging, biochemical, and genetic analyses, we found that in a model of acute reduction of mitochondrial translation fidelity (MTF) some population of mitochondria within a single cell are enriched, while some showed reduced levels of CYCS (cytochrome c, somatic) and CPOX (coproporphyrinogen oxidase) proteins, both located in the intermembrane space (IMS); henceforth called "mosaic distribution". Formation of mosaic mitochondria requires mitochondrial fission and active mitochondrial translation. In cell lines deficient in PRKN activity, this process is followed by severing the outer mitochondrial membrane (OMM) and ubiquitination of the inner mitochondrial membrane (IMM) proteins (including TRAP1 and CPOX), recruitment of autophagy receptors, and formation of mito-autophagosomes. In contrast, in PRKN-expressing cells, mitochondria with high CYCS and CPOX levels are preferentially targeted by PRKN, leading to OMM ubiquitination and canonical PRKN-PINK1-mediated autophagy.


Asunto(s)
Autofagia , Mitocondrias/metabolismo , Membranas Mitocondriales/metabolismo , Ubiquitina-Proteína Ligasas/deficiencia , Animales , Humanos , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/fisiología , Ubiquitinación
14.
J Clin Invest ; 131(19)2021 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-34403361

RESUMEN

Proper metabolic activities facilitate T cell expansion and antitumor function; however, the mechanisms underlying disruption of the T cell metabolic program and function in the tumor microenvironment (TME) remain elusive. Here, we show a zinc finger protein 91-governed (ZFP91-governed) mechanism that disrupts the metabolic pathway and antitumor activity of tumor-infiltrating T cells. Single-cell RNA-Seq revealed that impairments in T cell proliferation and activation correlated with ZFP91 in tissue samples from patients with colorectal cancer. T cell-specific deletion of Zfp91 in mice led to enhanced T cell proliferation and potentiated T cell antitumor function. Loss of ZFP91 increased mammalian target of rapamycin complex 1 (mTORC1) activity to drive T cell glycolysis. Mechanistically, T cell antigen receptor-dependent (TCR-dependent) ZFP91 cytosolic translocation promoted protein phosphatase 2A (PP2A) complex assembly, thereby restricting mTORC1-mediated metabolic reprogramming. Our results demonstrate that ZFP91 perturbs T cell metabolic and functional states in the TME and suggest that targeting ZFP91 may improve the efficacy of cancer immunotherapy.


Asunto(s)
Citotoxicidad Inmunológica , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos T/inmunología , Ubiquitina-Proteína Ligasas/fisiología , Animales , Neoplasias Colorrectales/inmunología , Glucólisis , Humanos , Activación de Linfocitos , Diana Mecanicista del Complejo 1 de la Rapamicina/fisiología , Ratones , Ratones Endogámicos C57BL , Proteína Fosfatasa 2/metabolismo , Linfocitos T/metabolismo , Microambiente Tumoral
15.
Cardiovasc Ther ; 2021: 6615400, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34221126

RESUMEN

Abdominal aortic aneurysm (AAA) is defined as a progressive segmental dilation of the abdominal aorta and is associated with high mortality. The characterized features of AAA indicate several underlying mechanisms of AAA formation and progression, including reactive oxygen species production, inflammation, and atherosclerosis. Mitochondrial functions are critical for determining cell fate, and mitochondrial dynamics, especially selective mitochondrial autophagy, which is termed as mitophagy, has emerged as an important player in the pathogenesis of several cardiovascular diseases. The PARKIN/PARIS/PGC1α pathway is associated with AAA formation and has been proposed to play a role in mitochondrial dynamics mediated by the PINK/PARKIN pathway in the pathogenesis underlying AAA. This review is aimed at deepening our understanding of AAA formation and progression, which is vital for the development of potential medical therapies for AAA.


Asunto(s)
Aneurisma de la Aorta Abdominal/fisiopatología , Disección Aórtica/fisiopatología , Dinámicas Mitocondriales/fisiología , Animales , Aterosclerosis/metabolismo , Modelos Animales de Enfermedad , Humanos , Inflamación/metabolismo , Masculino , Mitocondrias/metabolismo , Mitocondrias/patología , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/fisiología , Especies Reactivas de Oxígeno/metabolismo , Ubiquitina-Proteína Ligasas/fisiología
16.
Mol Cell Biol ; 41(10): e0008121, 2021 09 24.
Artículo en Inglés | MEDLINE | ID: mdl-34251884

RESUMEN

Cullin-4 ubiquitin ligase (CRL4) complexes are differentially composed and highly dynamic protein assemblies that control many biological processes, including the global genome nucleotide excision repair (GG-NER) pathway. Here, we identified the kinase mitogen-activated protein kinase kinase kinase 1 (MEKK1) as a novel constitutive interactor of a cytosolic CRL4 complex that disassembles after DNA damage due to the caspase-mediated cleavage of MEKK1. The kinase activity of MEKK1 was important to trigger autoubiquitination of the CRL4 complex by K48- and K63-linked ubiquitin chains. MEKK1 knockdown prohibited DNA damage-induced degradation of the CRL4 component DNA-damage binding protein 2 (DDB2) and the CRL4 substrate p21 and also cell recovery and survival. A ubiquitin replacement strategy revealed a contribution of K63-branched ubiquitin chains for DNA damage-induced DDB2/p21 decay, cell cycle regulation, and cell survival. These data might also have implications for cancer, as frequently occurring mutations of MEKK1 might have an impact on genome stability and the therapeutic efficacy of CRL4-dependent immunomodulatory drugs such as thalidomide derivatives.


Asunto(s)
Reparación del ADN/fisiología , Quinasa 1 de Quinasa de Quinasa MAP/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Supervivencia Celular , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , ADN/química , Daño del ADN/fisiología , Reparación del ADN/genética , Proteínas de Unión al ADN/metabolismo , Células HEK293 , Células HeLa , Humanos , Quinasa 1 de Quinasa de Quinasa MAP/genética , Proteínas Nucleares/metabolismo , Ubiquitina-Proteína Ligasas/fisiología , Ubiquitinación
17.
Mol Oncol ; 15(10): 2801-2817, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34312968

RESUMEN

Histone modification is aberrantly regulated in cancer and generates an unbalanced state of gene transcription. VprBP, a recently identified kinase, phosphorylates histone H2A on threonine 120 (T120) and is involved in oncogenic transcriptional dysregulation; however, its specific role in colon cancer is undefined. Here, we show that VprBP is overexpressed in colon cancer and directly contributes to epigenetic gene silencing and cancer pathogenesis. Mechanistically, the observed function of VprBP is mediated through H2AT120 phosphorylation (H2AT120p)-driven transcriptional repression of growth regulatory genes, resulting in a significantly higher proliferative capacity of colon cancer cells. Our preclinical studies using organoid and xenograft models demonstrate that treatment with the VprBP inhibitor B32B3 impairs colonic tumor growth by blocking H2AT120p and reactivating a transcriptional program resembling that of normal cells. Collectively, our work describes VprBP as a master kinase contributing to the development and progression of colon cancer, making it a new molecular target for novel therapeutic strategies.


Asunto(s)
Neoplasias del Colon , Histonas , Proteínas Serina-Treonina Quinasas , Ubiquitina-Proteína Ligasas , Neoplasias del Colon/genética , Epigénesis Genética , Silenciador del Gen , Histonas/metabolismo , Humanos , Fosforilación , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/fisiología , Ubiquitina-Proteína Ligasas/fisiología
18.
Int J Mol Sci ; 22(11)2021 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-34073690

RESUMEN

E3 ubiquitin ligases, the most important part of the ubiquitination process, participate in various processes of plant immune response. RBR E3 ligase is one of the E3 family members, but its functions in plant immunity are still little known. NtRNF217 is a RBR E3 ligase in tobacco based on the sequence analysis. To assess roles of NtRNF217 in tobacco responding to Ralstonia solanacearum, overexpression experiments in Nicotiana tabacum (Yunyan 87, a susceptible cultivar) were performed. The results illuminated that NtRNF217-overexpressed tobacco significantly reduced multiplication of R. solanacearum and inhibited the development of disease symptoms compared with wild-type plants. The accumulation of H2O2 and O2- in NtRNF217-OE plants was significantly higher than that in WT-Yunyan87 plants after pathogen inoculation. The activities of CAT and SOD also increased rapidly in a short time after R. solanacearum inoculation in NtRNF217-OE plants. What is more, overexpression of NtRNF217 enhanced the transcript levels of defense-related marker genes, such as NtEFE26, NtACC Oxidase, NtHIN1, NtHSR201, and NtSOD1 in NtRNF217-OE plants after R. solanacearum inoculation. The results suggested that NtRNF217 played an important role in regulating the expression of defense-related genes and the antioxidant enzymes, which resulted in resistance to R. solanacearum infection.


Asunto(s)
Resistencia a la Enfermedad , Nicotiana/metabolismo , Enfermedades de las Plantas , Ralstonia solanacearum , Ubiquitina-Proteína Ligasas/fisiología , Infecciones Bacterianas/metabolismo , Regulación de la Expresión Génica de las Plantas , Peróxido de Hidrógeno , Filogenia , Proteínas de Plantas/fisiología , Especies Reactivas de Oxígeno , Nicotiana/genética , Nicotiana/fisiología , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo
20.
Plant Cell Environ ; 44(9): 3034-3048, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34129248

RESUMEN

Abiotic stress, a serious threat to plants, occurs for extended periods in nature. Abscisic acid (ABA) plays a critical role in abiotic stress responses in plants. Therefore, stress responses mediated by ABA have been studied extensively, especially in short-term responses. However, long-term stress responses mediated by ABA remain largely unknown. To elucidate the mechanism by which plants respond to prolonged abiotic stress, we used long-term ABA treatment that activates the signalling against abiotic stress such as dehydration and investigated mechanisms underlying the responses. Long-term ABA treatment activates constitutive photomorphogenic 1 (COP1). Active COP1 mediates the ubiquitination of golden2-like1 (GLK1) for degradation, contributing to lowering expression of photosynthesis-associated genes such as glutamyl-tRNA reductase (HEMA1) and protochlorophyllide oxidoreductase A (PORA), resulting in the suppression of chloroplast development. Moreover, COP1 activation and GLK1 degradation upon long-term ABA treatment depend on light intensity. Additionally, plants with COP1 mutation or exposed to higher light intensity were more sensitive to salt stress. Collectively, our results demonstrate that long-term treatment of ABA leads to activation of COP1 in a light intensity-dependent manner for GLK1 degradation to suppress chloroplast development, which we propose to constitute a mechanism of balancing normal growth and stress responses upon the long-term abiotic stress.


Asunto(s)
Ácido Abscísico/metabolismo , Proteínas de Arabidopsis/fisiología , Cloroplastos/fisiología , Reguladores del Crecimiento de las Plantas/fisiología , Factores de Transcripción/fisiología , Ubiquitina-Proteína Ligasas/fisiología , Arabidopsis/fisiología , Proteínas de Arabidopsis/metabolismo , Dimerización , Relación Dosis-Respuesta en la Radiación , Luz , Factores de Transcripción/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación
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