RESUMEN
Oxidative stress contributes greatly to doxorubicin (DOX)-induced cardiotoxicity. Down-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2) is a key factor in DOX-induced myocardial oxidative injury. Recently, we found that mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1)-dependent k48-linked ubiquitination was responsible for down-regulation of myocardial Nrf2 in DOX-treated mice. Micafungin, an antifungal drug, was identified as a potential MALT1 inhibitor. This study aims to explore whether micafungin can reduce DOX-induced myocardial oxidative injury and if its anti-oxidative effect involves a suppression of MALT1-dependent k48-linked ubiquitination of Nrf2. To establish the cardiotoxicity models in vivo and in vitro, mice were treated with a single dose of DOX (15 mg/kg, i.p.) and cardiomyocytes were incubated with DOX (1 µM) for 24 h, respectively. Using mouse model of DOX-induced cardiotoxicity, micafungin (10 or 20 mg/kg) was shown to improve cardiac function, concomitant with suppression of oxidative stress, mitochondrial dysfunction, and cell death in a dose-dependent manner. Similar protective roles of micafungin (1 or 5 µM) were observed in DOX-treated cardiomyocytes. Mechanistically, micafungin weakened the interaction between MALT1 and Nrf2, decreased the k48-linked ubiquitination of Nrf2 while elevated the protein levels of Nrf2 in both DOX-treated mice and cardiomyocytes. Furthermore, MALT1 overexpression counteracted the cardioprotective effects of micafungin. In conclusion, micafungin reduces DOX-induced myocardial oxidative injury via suppression of MALT1, which decreases the k48-linked ubiquitination of Nrf2 and elevates Nrf2 protein levels. Thus, micafungin may be repurposed for treating DOX-induced cardiotoxicity.
Asunto(s)
Doxorrubicina , Micafungina , Ratones Endogámicos C57BL , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Ubiquitinación , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Doxorrubicina/toxicidad , Ubiquitinación/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratones , Masculino , Micafungina/farmacología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Cardiotoxicidad/prevención & control , Cardiotoxicidad/metabolismo , Cardiotoxicidad/etiología , Miocardio/metabolismo , Miocardio/patologíaRESUMEN
Mucosa-associated lymphoid tissue lymphoma-translocation protein 1 (MALT1) is an attractive target for the development of modulatory compounds in the treatment of lymphoma and other cancers. While the three-dimensional structure of MALT1 has been previously determined through X-ray analysis, its dynamic behaviour in solution has remained unexplored. We present here dynamic analyses of the apo MALT1 form along with the E549A mutation. This investigation used NMR 15N relaxation and NOE measurements between side-chain methyl groups. Our findings confirm that MALT1 exists as a monomer in solution, and demonstrate that the domains display semi-independent movements in relation to each other. Our dynamic study, covering multiple time scales, along with the assessment of conformational populations by Molecular Dynamic simulations, Alpha Fold modelling and PCA analysis, put the side chain of residue W580 in an inward position, shedding light at potential mechanisms underlying the allosteric regulation of this enzyme.
Asunto(s)
Simulación de Dinámica Molecular , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas , Regulación Alostérica , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/química , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , Humanos , Espectroscopía de Resonancia Magnética/métodos , Resonancia Magnética Nuclear Biomolecular , Conformación Proteica , MutaciónRESUMEN
MALT1 has been implicated as an upstream regulator of NF-κB signaling in immune cells and tumors. This study determined the regulatory mechanisms and biological functions of MALT1 in non-small cell lung cancer (NSCLC). In cell culture and orthotopic xenograft models, MALT1 suppression via gene expression interference or protein activity inhibition significantly impaired malignant phenotypes and enhanced radiation sensitivity of NSCLC cells. CSN5, the core subunit of COP9 signalosome, was firstly verified to stabilize MALT1 via disturbing the interaction with E3 ligase FBXO3. Loss of FBXO3 in NSCLC cells reduced MALT1 ubiquitination and promoted its accumulation, which was reversed by CSN5 interference. An association between CSN5/FBXO3/MALT1 regulatory axis and poor prognosis in NSCLC patients was identified. Our findings revealed the detail mechanism of continuous MALT1 activation in NF-κB signaling, highlighting its significance as predictor and potential therapeutic target in NSCLC.
Asunto(s)
Complejo del Señalosoma COP9 , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas , FN-kappa B , Transducción de Señal , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Humanos , Complejo del Señalosoma COP9/metabolismo , Complejo del Señalosoma COP9/genética , FN-kappa B/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Animales , Línea Celular Tumoral , Ratones , Ratones Desnudos , Ubiquitinación , Péptido Hidrolasas/metabolismo , Péptido Hidrolasas/genética , Progresión de la Enfermedad , Ratones Endogámicos BALB C , Femenino , Proteínas F-Box/metabolismo , Proteínas F-Box/genética , Péptidos y Proteínas de Señalización IntracelularRESUMEN
CARD-BCL10-MALT1 (CBM) signalosomes connect distal signaling of innate and adaptive immune receptors to proximal signaling pathways and immune activation. Four CARD scaffold proteins (CARD9, 10, 11, 14) can form seeds that nucleate the assembly of BCL10-MALT1 filaments in a cell- and stimulus-specific manner. MALT1 (also known as PCASP1) serves a dual function within the assembled CBM complexes. By recruiting TRAF6, MALT1 acts as a molecular scaffold that initiates IκB kinase (IKK)/NF-κB and c-Jun N-terminal kinase (JNK)/AP-1 signaling. In parallel, proximity-induced dimerization of the paracaspase domain activates the MALT1 protease which exerts its function by cleaving a set of specific substrates. While complete MALT1 ablation leads to immune deficiency, selective destruction of either scaffolding or protease function provokes autoimmune inflammation. Thus, balanced MALT1-TRAF6 recruitment and MALT1 substrate cleavage are critical to maintain immune homeostasis and to promote optimal immune activation. Further, MALT1 protease activity drives the survival of aggressive lymphomas and other non-hematologic solid cancers. However, little is known about the relevance of the cleavage of individual substrates for the pathophysiological functions of MALT1. Unbiased serendipity, screening and computational predictions have identified and validated ~20 substrates, indicating that MALT1 targets a quite distinct set of proteins. Known substrates are involved in CBM auto-regulation (MALT1, BCL10 and CARD10), regulation of signaling and adhesion (A20, CYLD, HOIL-1 and Tensin-3), or transcription (RelB) and mRNA stability/translation (Regnase-1, Roquin-1/2 and N4BP1), indicating that MALT1 often targets multiple proteins involved in similar cellular processes. Here, we will summarize what is known about the fate and functions of individual MALT1 substrates and how their cleavage contributes to the biological functions of the MALT1 protease. We will outline what is needed to better connect critical pathophysiological roles of the MALT1 protease with the cleavage of distinct substrates.
Asunto(s)
Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas , Transducción de Señal , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , Humanos , Animales , Especificidad por Sustrato , Proteína 10 de la LLC-Linfoma de Células B/metabolismo , Proteína 10 de la LLC-Linfoma de Células B/genética , Proteínas Adaptadoras de Señalización CARD/metabolismo , Proteínas Adaptadoras de Señalización CARD/genética , Proteolisis , Factor 6 Asociado a Receptor de TNF/metabolismoRESUMEN
ABSTRACT: Because multiple myeloma (MM) poses a formidable therapeutic challenge despite recent progress, exploring novel targets is crucial. Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) emerges as a promising paracaspase with druggable potential, especially unexplored in MM. Our study provided compelling evidence demonstrating a statistically significant elevation of MALT1 expression in human primary MM cells. Moreover, elevated MALT1 expression was associated with a poorer prognosis in MM. Genetic deletion of MALT1 reduced cell growth, colony formation, and tumor growth in vivo. Pharmacological inhibition with 1 µM of a small-molecular MALT1 inhibitor, Mi-2, effectively inhibited cell growth, inducing mitochondria-dependent apoptotic cell death. Mechanistically, MALT1 inhibition disrupted diverse signal transduction pathways, notably impeding nuclear factor κB (NF-κB). Significantly, the inhibition of MALT1 demonstrated a substantial suppression of NF-κB activation by elevating inhibitor of NF-κB, disrupting the nuclear localization of p65 and c-REL. This effect was observed in both the basal state and when stimulated by B-cell maturation antigen, highlighting the pivotal role of MALT1 inhibition in influencing MM cell survival. It was noteworthy that Mi-2 induces properties associated with immunogenic cell death (ICD), as evidenced by increased calreticulin, adenosine triphosphate release, and high-mobility group protein B1 upregulation, consequently triggering ICD-associated immune activation and enhancing CD8+ T-cell cytotoxicity in vitro. In conclusion, our research highlights MALT1 as a promising druggable target for therapeutic interventions in MM, providing insights into its molecular mechanisms in MM progression.
Asunto(s)
Antígeno de Maduración de Linfocitos B , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas , Mieloma Múltiple , FN-kappa B , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/antagonistas & inhibidores , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , FN-kappa B/metabolismo , Animales , Ratones , Antígeno de Maduración de Linfocitos B/metabolismo , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacosRESUMEN
The CARMA-BCL10-MALT1 (CBM) signalosome functions as a pivotal supramolecular module, integrating diverse receptor-induced signaling pathways to regulate BCL10-dependent NF-kB activation in innate and adaptive immunity. Conversely, the API2-MALT1 fusion protein in t(11; 18)(q21; q21) MALT lymphoma constitutively induces BCL10-independent NF-kB activation. MALT1 dimer formation is indispensable for the requisite proteolytic activity and is critical for NF-kB activation regulation in both scenarios. However, the molecular assembly of MALT1 individual domains in CBM activation remains elusive. Here we report the crystal structure of the MALT1 death domain (DD) at a resolution of 2.1 Å, incorporating reconstructed residues in previously disordered loops 1 and 2. Additionally, we observe a conformational regulation element (CRE) regulating stem-helix formation in NLRPs pyrin (PYD) within the MALT1 DD structure. The structure reveals a stem-helix-mediated dimer further corroborated in solution. To elucidate how the BCL10 filament facilitates MALT1 dimerization, we reconstitute a BCL10-CARD-MALT1-DD-IG1-IG2 complex model. We propose a N+7 rule for BCL10-dependent MALT1 dimerization via the IG1-IG2 domain and for MALT1-dependent cleavage in trans. Biochemical data further indicates concentration-dependent dimerization of the MALT1 IG1-IG2 domain, facilitating MALT1 dimerization in BCL10-independent manner. Our findings provide a structural and biochemical foundation for understanding MALT1 dimeric mechanisms, shedding light on potential BCL10-independent MALT1 dimer formation and high-order BCL10-MALT1 assembly.
Asunto(s)
Proteína 10 de la LLC-Linfoma de Células B , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas , Dominios Proteicos , Multimerización de Proteína , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/química , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , Proteína 10 de la LLC-Linfoma de Células B/metabolismo , Proteína 10 de la LLC-Linfoma de Células B/química , Proteína 10 de la LLC-Linfoma de Células B/genética , Humanos , Cristalografía por Rayos X , Modelos Moleculares , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/química , Proteínas de Neoplasias/genética , Caspasas/metabolismo , Caspasas/químicaRESUMEN
INTRODUCTION: Mucosa-associated lymphoid tissue 1 (MALT1) modulates T helper cell differentiation, pro-inflammatory cytokine production, and epidermal hyperplasia to participate in the pathology of psoriasis. This study aimed to explore the correlation of blood MALT1 with treatment outcomes in psoriasis patients. METHODS: MALT1 was detected in peripheral blood mononuclear cells by reverse transcription-quantitative polymerase chain reaction in 210 psoriasis patients before starting or converting to a new therapy, 50 disease controls, and 50 healthy controls. The psoriasis area severity index (PASI) score was evaluated at month (M)1, M3, and M6 in psoriasis patients. RESULTS: MALT1 was increased in psoriasis patients versus disease controls and healthy controls (both p < .001); and positively related to body mass index (p = .019) and PASI score (p < .001) in psoriasis patients. PASI75 rate at M1, M3, and M6 was 22.9%, 46.2%, and 71.0%, respectively; while PASI90 rate at M1, M3, and M6 was 3.8%, 29.0%, and 50.5%, respectively, in psoriasis patients. PASI75/90 rates at M1, M3, and M6 were increased in psoriasis patients receiving biologics versus those without (all p < .05). Pretreatment MALT1 was higher in psoriasis patients who achieved PASI75 (p = .001) and PASI90 (p < .001) at M6 compared to those who did not achieve that. Subgroup analyses discovered that pretreatment MALT1 had a stronger ability to predict PASI75 and 90 realizations in psoriasis patients receiving biologics (area under the curve [AUC]: 0.723 and 0.808) versus those without (AUC: 0.594 and 0.675). CONCLUSION: Blood MALT1 measurement may assist in predicting outcomes in psoriasis patients, especially in those receiving biologics.
Asunto(s)
Productos Biológicos , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas , Psoriasis , Humanos , Productos Biológicos/uso terapéutico , Leucocitos Mononucleares/metabolismo , Estudios Prospectivos , Psoriasis/diagnóstico , Psoriasis/tratamiento farmacológico , Resultado del TratamientoRESUMEN
The activated B cell (ABC) subset of diffuse large B-cell lymphoma (DLBCL) is characterized by chronic B-cell receptor signaling and associated with poor outcomes when treated with standard therapy. In ABC-DLBCL, MALT1 is a core enzyme that is constitutively activated by stimulation of the B-cell receptor or gain-of-function mutations in upstream components of the signaling pathway, making it an attractive therapeutic target. We discovered a novel small-molecule inhibitor, ABBV-MALT1, that potently shuts down B-cell signaling selectively in ABC-DLBCL preclinical models leading to potent cell growth and xenograft inhibition. We also identified a rational combination partner for ABBV-MALT1 in the BCL2 inhibitor, venetoclax, which when combined significantly synergizes to elicit deep and durable responses in preclinical models. This work highlights the potential of ABBV-MALT1 monotherapy and combination with venetoclax as effective treatment options for patients with ABC-DLBCL.
Asunto(s)
Sinergismo Farmacológico , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas , Proteínas Proto-Oncogénicas c-bcl-2 , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/antagonistas & inhibidores , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , Humanos , Animales , Ratones , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Línea Celular Tumoral , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Proliferación Celular/efectos de los fármacos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Modelos Animales de EnfermedadRESUMEN
The proinflammatory cytokines and arachidonic acid (AA)-derived eicosanoids play a key role in cartilage degeneration in osteoarthritis (OA). The lysophosphatidylcholine acyltransferase 3 (LPCAT3) preferentially incorporates AA into the membranes. Our recent studies showed that MALT1 [mucosa-associated lymphoid tissue lymphoma translocation protein 1]) plays a crucial role in propagating inflammatory signaling triggered by IL-1ß and other inflammatory mediators in endothelial cells. The present study shows that LPCAT3 expression was up-regulated in both human and mice articular cartilage of OA, and correlated with severity of OA. The IL-1ß-induces cell death via upregulation of LPCAT3, MMP3, ADAMTS5, and eicosanoids via MALT1. Gene silencing or pharmacological inhibition of LPCAT3 or MALT1 in chondrocytes and human cartilage explants notably suppressed the IL-1ß-induced cartilage catabolism through inhibition of expression of MMP3, ADAMTS5, and also secretion of cytokines and eicosanoids. Mechanistically, overexpression of MALT1 in chondrocytes significantly upregulated the expression of LPCAT3 along with MMP3 and ADAMTS5 via c-Myc. Inhibition of c-Myc suppressed the IL-1ß-MALT1-dependent upregulation of LPCAT3, MMP3 and ADAMTS5. Consistent with the in vitro data, pharmacological inhibition of MALT1 or gene silencing of LPCAT3 using siRNA-lipid nanoparticles suppressed the synovial articular cartilage erosion, pro-inflammatory cytokines, and eicosanoids such as PGE2, LTB4, and attenuated osteoarthritis induced by the destabilization of the medial meniscus in mice. Overall, our data reveal a previously unrecognized role of the MALT1-LPCAT3 axis in osteoarthritis. Targeting the MALT1-LPCAT3 pathway with MALT1 inhibitors or siRNA-liposomes of LPCAT3 may become an effective strategy to treat OA by suppressing eicosanoids, matrix-degrading enzymes, and proinflammatory cytokines.
Asunto(s)
Cartílago Articular , Osteoartritis , Animales , Humanos , Ratones , 1-Acilglicerofosfocolina O-Aciltransferasa/metabolismo , 1-Acilglicerofosfocolina O-Aciltransferasa/farmacología , Cartílago Articular/metabolismo , Cartílago Articular/patología , Células Cultivadas , Condrocitos/metabolismo , Citocinas/metabolismo , Eicosanoides/metabolismo , Eicosanoides/farmacología , Eicosanoides/uso terapéutico , Células Endoteliales/metabolismo , Interleucina-1beta/metabolismo , Metaloproteinasa 3 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/farmacología , Metaloproteinasa 3 de la Matriz/uso terapéutico , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , Osteoartritis/metabolismo , ARN Interferente Pequeño/metabolismoRESUMEN
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) has emerged as a novel and promising therapeutic target for the treatment of lymphomas and autoimmune diseases. Herein, we reported a new class of MALT1 inhibitors featuring a novel "2-thioxo-2,3-dihydrothiazolo[4,5-d]pyrimidin-7(6H)-one" scaffold developed by structure-based drug design. Structure-activity relationship studies finally led to the discovery of MALT1 inhibitor 10m, which covalently and potently inhibited MALT1 protease with the IC50 value of 1.7 µM. 10m demonstrated potent and selective antiproliferative activity against ABC-DLBCL and powerful ability to induce HBL1 apoptosis. 10m also effectively downregulated the activities of MALT1 and its downstream signal pathways. Furthermore, 10m induced upregulation of mTOR and PI3K-Akt signals and exhibited a synergistic antitumor effect with Rapamycin in HBL1 cells. More importantly, 10m remarkably suppressed the tumor growth both in the implanted HBL1 and TMD8 xenograft models. Collectively, this work provides valuable MALT1 inhibitors with a distinct core structure.
Asunto(s)
Caspasas , Linfoma de Células B Grandes Difuso , Humanos , Caspasas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Línea Celular Tumoral , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas , Transducción de Señal , FN-kappa B/metabolismoRESUMEN
The objective of this study was to clarify the long-term prognosis of patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma with additional copies of MALT1. In this multicenter retrospective study, we enrolled 145 patients with gastric MALT lymphoma who underwent fluorescence in situ hybridization (FISH) analysis to detect t(11;18) translocation. The patient cohort was divided into three groups: Group A (n = 87), comprising individuals devoid of the t(11;18) translocation or extra MALT1 copies; Group B (n = 27), encompassing patients characterized by the presence of the t(11;18) translocation; and Group C (n = 31), including patients with extra MALT1 copies. The clinical outcomes in each cohort were collected. Over the course of a mean follow-up of 8.5 ± 4.2 years, one patient died of progressive MALT lymphoma, while 15 patients died due to etiologies unrelated to lymphoma. The progression or relapse of MALT lymphoma was observed in 11 patients: three in Group A, two in Group B, and six in Group C. In Groups A, B, and C, the 10-year overall survival rates were 82.5%, 93.8%, and 86.4%, respectively, and the 10-year event-free survival rates were 96.1%, 96.0%, and 82.9%, respectively. The event-free survival rate in Group C was significantly lower than that in Group A. However, no differences were observed in the 10-year event-free survival rates among individuals limited to stage I or II1 disease (equivalent to excluding patients with stage IV disease in this study, as there were no patients with stage II2), with rates of 98.6%, 95.8%, and 92.3% for Groups A, B, and C, respectively. In conclusion, the presence of extra copies of MALT1 was identified as an inferior prognostic determinant of event-free survival. Consequently, trisomy/tetrasomy 18 may serve as an indicator of progression and refractoriness to therapeutic intervention in patients with gastric MALT lymphoma, particularly stage IV gastric MALT lymphoma.
Asunto(s)
Linfoma de Células B de la Zona Marginal , Linfoma no Hodgkin , Neoplasias Gástricas , Humanos , Linfoma de Células B de la Zona Marginal/genética , Linfoma de Células B de la Zona Marginal/patología , Hibridación Fluorescente in Situ , Estudios Retrospectivos , Recurrencia Local de Neoplasia/genética , Translocación Genética , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genéticaRESUMEN
Glioblastoma stem-like cells (GSCs) compose a tumor-initiating and -propagating population remarkably vulnerable to variation in the stability and integrity of the lysosomal compartment. Previous work has shown that the expression and activity of the paracaspase MALT1 control GSC viability via lysosome abundance. However, the underlying mechanisms remain elusive. By combining RNA sequencing (RNA-seq) with proteome-wide label-free quantification, we now report that MALT1 repression in patient-derived GSCs alters the homeostasis of cholesterol, which accumulates in late endosomes (LEs)-lysosomes. This failure in cholesterol supply culminates in cell death and autophagy defects, which can be partially reverted by providing exogenous membrane-permeable cholesterol to GSCs. From a molecular standpoint, a targeted lysosome proteome analysis unraveled that Niemann-Pick type C (NPC) lysosomal cholesterol transporters are diluted when MALT1 is impaired. Accordingly, we found that NPC1/2 inhibition and silencing partially mirror MALT1 loss-of-function phenotypes. This supports the notion that GSC fitness relies on lysosomal cholesterol homeostasis.
Asunto(s)
Glioblastoma , Enfermedad de Niemann-Pick Tipo C , Humanos , Proteoma/metabolismo , Proteínas Portadoras/metabolismo , Glioblastoma/genética , Glioblastoma/metabolismo , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Homeostasis , Lisosomas/metabolismo , Colesterol/metabolismo , Enfermedad de Niemann-Pick Tipo C/metabolismoRESUMEN
Chronic lymphocytic leukaemia (CLL) is a clonal B-cell malignancy and remains a chronic disease despite improvements in clinical outcomes since the use of targeted therapies. Both clinical and biological parameters are important for determining prognosis. Unlike other mature B-cell lymphomas, translocations involving the immunoglobulin heavy chain (IGH) locus are uncommon in CLL. There have been few case reports of CLL harbouring t(14;18)/IGH::BCL2 and t(14;19)/IGH::BCL3. Here we describe the first two cases of patients with CLL with documented t(14;18)(q32;q21)/IGH::MALT1. Both cases in this report were associated with lower-risk biological parameters. Thus, FISH testing for MALT1 in cases with unknown IGH translocation partners in the setting of CLL should be implemented in clinical practice to better define such cases.
Asunto(s)
Leucemia Linfocítica Crónica de Células B , Linfoma de Células B de la Zona Marginal , Humanos , Caspasas , Linfoma de Células B de la Zona Marginal/patología , Translocación Genética , Pronóstico , Cromosomas Humanos Par 14 , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a MucosasRESUMEN
Oral lichen planus (OLP) is a T cell-mediated immune mucosal disease of unknown pathogenesis. Whether mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), an intracellular signaling protein, is involved in the T-cell immune dysfunction of OLP remains elusive. MALT1 expression in local and peripheral T cells of OLP and controls was analyzed using immunohistochemistry, multiplex immunohistochemistry, and flow cytometry. The expression of MALT1 in activated Jurkat T cells incubated with either OLP plasma or interleukin (IL)-7/IL-15 was determined by flow cytometry. The effects of MALT1 and mechanistic target of rapamycin (mTOR) on T-cell immunity were investigated through western blot, CCK8 assay, and flow cytometry. The expression of MALT1 protein was elevated in local OLP T cells and mucosal-associated invariant T (MAIT) cells, while reduced in peripheral OLP T cells, MAIT cells, and follicular helper-like MAIT (MAITfh) cells. Stimulation with OLP plasma and IL-7/ IL-15 had no effect on MALT1 expression in activated Jurkat T cells. MALT1 protease-specific inhibitor (MI-2) induced mTOR phosphorylation, increased B-cell lymphoma 10 (BCL10) expression, inhibited T-cell proliferation, and promoted T-cell apoptosis. The combination of MI-2 and rapamycin increased MALT1 expression, further suppressed T-cell proliferation, and facilitated T-cell apoptosis. MALT1 expression is aberrant in both local lesions and peripheral blood of OLP. Inhibition of the mTOR pathway further enhances the suppression of T-cell proliferation and the promotion of apoptosis induced by the MALT1 inhibitor MI-2.
Asunto(s)
Liquen Plano Oral , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas , Linfocitos T , Serina-Treonina Quinasas TOR , Humanos , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Liquen Plano Oral/metabolismo , Liquen Plano Oral/inmunología , Liquen Plano Oral/patología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Células Jurkat , Transducción de Señal , Masculino , Femenino , Apoptosis/efectos de los fármacos , Persona de Mediana Edad , AdultoRESUMEN
Caspase recruitment domain-containing protein (CARD)9, CARD10, CARD11, and CARD14 all belong to the CARD-coiled coil (CC) protein family and originated from a single common ancestral protein early in vertebrate evolution. All four proteins form CARD-CC/BCL10/MALT1 (CBM) complexes leading to nuclear factor-kappa-B (NF-κB) activation after upstream phosphorylation by various protein kinase C (PKC) isoforms. CBM complex signaling is critical for innate and adaptive immunity, but aberrant activation can cause autoimmune or autoinflammatory diseases, or be oncogenic. CARD9 shows a superior auto-inhibition compared with other CARD-CC family proteins, with very low spontaneous activity when overexpressed in HEK293T cells. In contrast, the poor auto-inhibition of other CARD-CC family proteins, especially CARD10 (CARMA3) and CARD14 (CARMA2), is hampering characterization of upstream activators or activating mutations in overexpression studies. We grafted different domains from CARD10, 11, and 14 on CARD9 to generate chimeric CARD9 backbones for functional characterization of activating mutants using NF-κB reporter gene activation in HEK293T cells as readout. CARD11 (CARMA1) activity was not further reduced by grafting on CARD9 backbones. The chimeric CARD9 approach was subsequently validated by using several known disease-associated mutations in CARD10 and CARD14, and additional screening allowed us to identify several previously unknown activating natural variants in human CARD9 and CARD10. Using Genebass as a resource of exome-based disease association statistics, we found that activated alleles of CARD9 correlate with irritable bowel syndrome (IBS), constipation, osteoarthritis, fibromyalgia, insomnia, anxiety, and depression, which can occur as comorbidities.
Asunto(s)
Proteínas Adaptadoras de Señalización CARD , FN-kappa B , Humanos , FN-kappa B/metabolismo , Células HEK293 , Proteínas Adaptadoras de Señalización CARD/genética , Transducción de Señal , Guanilato Ciclasa/metabolismo , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteína Quinasa C/metabolismo , Proteínas de la Membrana/metabolismoRESUMEN
The protease MALT1 promotes lymphocyte activation and lymphomagenesis by cleaving a limited set of cellular substrates, most of which control gene expression. Here, we identified the integrin-binding scaffold protein Tensin-3 as a MALT1 substrate in activated human B cells. Activated B cells lacking Tensin-3 showed decreased integrin-dependent adhesion but exhibited comparable NF-κB1 and Jun N-terminal kinase transcriptional responses. Cells expressing a noncleavable form of Tensin-3, on the other hand, showed increased adhesion. To test the role of Tensin-3 cleavage in vivo, mice expressing a noncleavable version of Tensin-3 were generated, which showed a partial reduction in the T cell-dependent B cell response. Interestingly, human diffuse large B cell lymphomas and mantle cell lymphomas with constitutive MALT1 activity showed strong constitutive Tensin-3 cleavage and a decrease in uncleaved Tensin-3 levels. Moreover, silencing of Tensin-3 expression in MALT1-driven lymphoma promoted dissemination of xenografted lymphoma cells to the bone marrow and spleen. Thus, MALT1-dependent Tensin-3 cleavage reveals a unique aspect of the function of MALT1, which negatively regulates integrin-dependent B cell adhesion and facilitates metastatic spread of B cell lymphomas.
Asunto(s)
Caspasas , Linfoma de Células B Grandes Difuso , Ratones , Humanos , Animales , Adulto , Tensinas/genética , Caspasas/metabolismo , FN-kappa B/metabolismo , Adhesión Celular/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , Linfoma de Células B Grandes Difuso/genética , IntegrinasRESUMEN
MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) serves as a pivotal mediator for NF-κB activation in response to a wide spectrum of transmembrane receptor stimuli. In the present study, a homolog of MALT1, named LvMALT1, is cloned from the Pacific white shrimp (Litopenaeus vannamei) and its potential function in shrimp innate immunity is explored. The open reading frame of LvMALT1 is 2364 bp that encodes 787 amino acids. The predicted LvMALT1 protein structure comprises a death domain, three immunoglobulin domains, and a caspase-like domain, exhibiting remarkable similarity to other homologs. LvMALT1 is a cytoplasmic-localized protein and could interact with LvTRAF6. Overexpression of LvMALT1 induces the activation of promoter elements governing the expression of several key antimicrobial peptides (AMPs), including penaeidins (PENs) and crustins (CRUs). Conversely, silencing of LvMALT1 leads to a reduction in the phosphorylation levels of Dorsal and Relish, along with a concomitant decline in the in vivo expression levels of multiple AMPs. Furthermore, LvMALT1 is prominently upregulated in response to a challenge by the white spot syndrome virus (WSSV), facilitating the NF-κB-mediated expression of AMPs as a defense against viral infection. Taken together, we identified a MALT1 homolog from the shrimp L. vannamei, which plays a positive role in the TRAF6/NF-κB/AMPs axis-mediated innate immunity.
Asunto(s)
Virosis , Virus del Síndrome de la Mancha Blanca 1 , Humanos , FN-kappa B/metabolismo , Transducción de Señal , Regiones Promotoras Genéticas , Regulación de la Expresión Génica , Virus del Síndrome de la Mancha Blanca 1/genética , Inmunidad Innata , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismoRESUMEN
Non-Hodgkin lymphoma (NHL) is one of the most common cancer types. Deregulated signaling pathways can trigger certain NHL subtypes, including Diffuse Large B-cell lymphoma. NF-ĸB signaling pathway, which is responsible for the proliferation, growth, and survival of cells, has an essential role in lymphoma development. Although different signals control NF-ĸB activation in various lymphoid malignancies, the characteristic one is the CARD11-BCL10-MALT1 (CBM) complex. The CBM complex is responsible for the initiation of adaptive immune response. Our study is focused on the molecular docking of ten polyphenols as potential CARD11-BCL10-MALT1 complex inhibitors, essentially through MALT1 inhibition. Molecular docking was performed by Auto Dock Tools and AutoDock Vina tool, while SwissADME was used for drug-likeness and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis of the ligands. Out of 66 ligands that were used in this study, we selected and visualized five. Selection criteria were based on the binding energy score and position of the ligands on the used protein. 2D and 3D visualizations showed interactions of ligands with the protein. Five ligands are considered potential inhibitors of MALT1, thus affecting NF-ĸB signaling pathway. However, additional in vivo and in vitro studies are required to confirm their mechanism of inhibition.
Asunto(s)
Proteínas Adaptadoras de Señalización CARD , Linfoma de Células B Grandes Difuso , Humanos , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/química , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , Proteínas Adaptadoras de Señalización CARD/metabolismo , FN-kappa B/metabolismo , Guanilato Ciclasa/metabolismo , Simulación del Acoplamiento MolecularRESUMEN
It is widely accepted that pancreatic islet ß-cell failure and the onset of type 2 diabetes (T2DM) constitute an intricate interplay between the genetic expression of the disease and a host of intracellular events including increased metabolic (oxidative, endoplasmic reticulum) stress under the duress of glucolipotoxicity. Emerging evidence implicates unique roles for Caspase Recruitment Domain containing protein 9 (CARD9) in the onset of metabolic diseases, including obesity and insulin resistance. Mechanistically, CARD9 has been implicated in the regulation of p38MAPK and NFkB signaling pathways culminating in cellular dysfunction. Several regulatory factors, including B-cell lymphoma/leukemia 10 (BCL10) have been identified as modulators of CARD9 function in multiple cell types. Despite this evidence on regulatory roles of CARD9-BCL10 signalome in the onset of various pathological states, putative roles of this signaling module in islet ß-cell dysfunction in metabolic stress remain less understood. This brief review is aimed at highlighting roles for CARD9 in islet ß-cell function under acute (physiological insulin secretion) and long-term (cell dysfunction) exposure to glucose. Emerging roles of other signaling proteins, such as Rac1, BCL10 and MALT1 as contributors to CARD9 signaling in the islet ß-cells are also reviewed. Potential avenues for future research toward the development of novel therapeutics for the prevention CARD9-BCL10-Rac1 (CBR) signalome-induced ß-cell defects under metabolic stress are discussed.