RESUMEN
Psoriasis is a chronic inflammatory skin disease arising from poorly defined pathological cross-talk between keratinocytes and the immune system. BCL10 (B cell lymphoma/leukemia 10) and MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) are ubiquitously expressed inflammatory signaling proteins that can interact with the psoriasis susceptibility factor CARD14, but their functions in psoriasis are insufficiently understood. We report that although keratinocyte-intrinsic BCL10/MALT1 deletions completely rescue inflammatory skin pathology triggered by germline Card14 gain-of-function mutation in mice, the BCL10/MALT1 signalosome is unexpectedly not involved in the CARD14-dependent interleukin-17 receptor (IL-17R) proximal pathway. Instead, it plays a more pleiotropic role by amplifying keratinocyte responses to a series of inflammatory cytokines, including IL-17A, IL-1ß, and TNF. Moreover, selective keratinocyte-intrinsic activation of BCL10/MALT1 signaling with an artificial engager molecule is sufficient to initiate lymphocyte-mediated psoriasiform skin inflammation, and aberrant BCL10/MALT1 activity is frequently detected in the skin of human sporadic psoriasis. Together, these results establish that BCL10/MALT1 signalosomes can act as initiators and crucial amplifiers of psoriatic skin inflammation and indicate a critical function for this complex in sporadic psoriasis.
Asunto(s)
Proteína 10 de la LLC-Linfoma de Células B/inmunología , Inflamación/inmunología , Queratinocitos/inmunología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , Psoriasis/inmunología , Piel/inmunología , Animales , Proteína 10 de la LLC-Linfoma de Células B/deficiencia , Proteína 10 de la LLC-Linfoma de Células B/genética , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/deficiencia , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genéticaRESUMEN
T cell responses to antigen are initiated by engagement of the T cell receptor (TCR)1, leading to activation of diverse signaling cascades, including an incompletely defined pathway that triggers rapid remodeling of the actin cytoskeleton. Defects in the control of actin dynamics and organization are associated with several human immunodeficiency diseases, emphasizing the importance of cytoskeletal remodeling in the functioning of the adaptive immune system. Here, we investigate the role of the adaptor protein Bcl102 in the control of actin dynamics. Although Bcl10 is primarily known as a component of the pathway connecting the TCR to activation of the NF-κB3 transcription factor, a few studies have implicated Bcl10 in antigen receptor-dependent control of actin polymerization and F-actin-dependent functional responses. However, the role of Bcl10 in the regulation of cytoskeletal dynamics remains largely undefined. To investigate the contribution of Bcl10 in the regulation of TCR-dependent cytoskeletal dynamics, we monitored actin dynamics at the immune synapse of primary murine CD8 effector T cells. Quantification of these dynamics reveals two distinct temporal phases distinguished by differences in speed and directionality. Our results indicate that effector CD8 T cells lacking Bcl10 display faster actin flows and more dynamic lamellipodia, compared to wild-type cells. These studies define a role for Bcl10 in TCR-dependent actin dynamics, emphasizing that Bcl10 has important cytoskeleton-directed functions that are likely independent of its role in transmission of NF-κB -activating signals.
Asunto(s)
Actinas/metabolismo , Proteína 10 de la LLC-Linfoma de Células B/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología , Actinas/inmunología , Animales , Proteína 10 de la LLC-Linfoma de Células B/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , FN-kappa B/inmunología , FN-kappa B/metabolismo , Fosforilación , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal/inmunología , Sinapsis/metabolismoRESUMEN
Regulatory T cells (Tregs) have crucial functions in the inhibition of immune responses. Their development and suppressive functions are controlled by the T cell receptor (TCR), but the TCR signaling mechanisms that mediate these effects remain ill-defined. Here we show that CARD11-BCL10-MALT1 (CBM) signaling mediates TCR-induced NF-κB activation in Tregs and controls the conversion of resting Tregs to effector Tregs under homeostatic conditions. However, in inflammatory milieus, cytokines can bypass the CBM requirement for this differentiation step. By contrast, CBM signaling, in a MALT1 protease-dependent manner, is essential for mediating the suppressive function of Tregs. In malignant melanoma models, acute genetic blockade of BCL10 signaling selectively in Tregs or pharmacological MALT1 inhibition enhances anti-tumor immune responses. Together, our data uncover a segregation of Treg differentiation and suppressive function at the CBM complex level, and provide a rationale to explore MALT1 inhibitors for cancer immunotherapy.
Asunto(s)
Proteína 10 de la LLC-Linfoma de Células B/inmunología , Proteínas Adaptadoras de Señalización CARD/inmunología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Animales , Proteína 10 de la LLC-Linfoma de Células B/metabolismo , Proteínas Adaptadoras de Señalización CARD/metabolismo , Diferenciación Celular , Citocinas/inmunología , Melanoma Experimental , Ratones , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , FN-kappa B/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/metabolismoRESUMEN
BACKGROUND: Gastric mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) are infrequently encountered in routine practice. Some gastric neuroendocrine carcinomas (NECs) have a variety of differentiation patterns; however, pancreatic acinar differentiation in gastric NECs is rare. The molecular abnormalities of NECs with pancreatic acinar differentiation are not well understood. CASE PRESENTATION: A 67-year-old male with a gastric MiNEN with pancreatic acinar differentiation without any symptoms. The tumor consisted of two components, including both glandular and solid histological features. Although the former component was a common type of adenocarcinoma, the latter showed endocrine differentiation and expressed pancreatic acinar enzymes immunohistochemically. A positive signal with the anti-BCL10 antibody, which detects one of the pancreatic acinar enzymes, was also present specifically in the latter component. We also examined TP53 genomic mutations, DNA methylation status, and allelic imbalance (AI), which is an indicator of tumor aggressiveness. Although both components of this tumor showed no genomic mutation and a low methylation epigenotype, the frequency of AI was higher in the acinar-endocrine component than in the adenocarcinomatous component. The finding of AI indicated the progression of the conventional adenocarcinoma to an acinar-endocrine component and identified the aggressive potential of the acinar-endocrine component. CONCLUSIONS: We report a rare case of gastric MiNEN with pancreatic acinar differentiation. AI analysis revealed tumor progression and aggressiveness. In addition, the usefulness of the anti-BCL10 antibody for detecting the acinar-endocrine component was suggested.
Asunto(s)
Proteína 10 de la LLC-Linfoma de Células B/inmunología , Biomarcadores de Tumor/genética , Carcinoma de Células Acinares/diagnóstico , Tumores Neuroendocrinos/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Neoplasias Gástricas/diagnóstico , Anciano , Anticuerpos , Carcinoma de Células Acinares/genética , Carcinoma de Células Acinares/patología , Diferenciación Celular , Humanos , Inmunohistoquímica , Masculino , Mutación , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/patología , Páncreas/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Estómago/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologíaRESUMEN
CARD protein-BCL-10-MALT1 (CBM) signalosomes are multiprotein signalling platforms that control immune and inflammatory pathways in most tissues. After exposure to distinct immune triggers, these molecules form self-organizing filaments with MALT1 protease activity to regulate canonical nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signalling pathways and the degradation of mRNA-binding proteins, which provides two layers of control of inflammatory gene expression. These CBM-regulated mechanisms are essential for host defence and tissue homeostasis, and numerous genetic alterations in CBM signalling components have been implicated in inherited and acquired immune-mediated diseases. This Review discusses the regulation and signalling of CBM complexes, their physiological roles and their pathophysiological functions in human immunodeficiency diseases, inflammatory disorders and cancers of the immune system.
Asunto(s)
Proteína 10 de la LLC-Linfoma de Células B/inmunología , Proteínas Adaptadoras de Señalización CARD/metabolismo , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , Transducción de Señal/inmunología , Animales , Humanos , Síndromes de Inmunodeficiencia/inmunología , Inflamación/inmunología , FN-kappa B/inmunologíaRESUMEN
Antigen receptor-induced signaling plays an important role in inflammation and immunity. Formation of a CARD11-BCL10-MALT1 (CBM) signaling complex is a key event in T- and B cell receptor-induced gene expression by regulating NF-κB activation and mRNA stability. Deregulated CARD11, BCL10 or MALT1 expression or CBM signaling have been associated with immunodeficiency, autoimmunity and cancer, indicating that CBM formation and function have to be tightly regulated. Over the past years great progress has been made in deciphering the molecular mechanisms of assembly and disassembly of the CBM complex. In this context, several posttranslational modifications play an indispensable role in regulating CBM function and downstream signal transduction. In this review we summarize how the different CBM components as well as their interplay are regulated by protein ubiquitination and phosphorylation in the context of T cell receptor signaling.
Asunto(s)
Enfermedades Autoinmunes/genética , Proteína 10 de la LLC-Linfoma de Células B/genética , Proteínas Adaptadoras de Señalización CARD/genética , Guanilato Ciclasa/genética , Síndromes de Inmunodeficiencia/genética , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , Neoplasias/genética , Procesamiento Proteico-Postraduccional/inmunología , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Proteína 10 de la LLC-Linfoma de Células B/inmunología , Linfocitos B/inmunología , Linfocitos B/patología , Proteínas Adaptadoras de Señalización CARD/inmunología , Guanilato Ciclasa/inmunología , Humanos , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/patología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , FN-kappa B/genética , FN-kappa B/inmunología , Neoplasias/inmunología , Neoplasias/patología , Fosforilación , Receptores de Antígenos de Linfocitos B/genética , Receptores de Antígenos de Linfocitos B/inmunología , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Transducción de Señal , Linfocitos T/inmunología , Linfocitos T/patología , UbiquitinaciónRESUMEN
Assembly of the CARD11/CARMA1-BCL10-MALT1 (CBM) signaling complex upon T or B cell antigen receptor (TCR or BCR) engagement drives lymphocyte activation. Recruitment of pre-assembled BCL10-MALT1 complexes to CARD11 fosters activation of the MALT1 protease and canonical NF-κB signaling. Structural data and in vitro assays have suggested that CARD11 acts as a seed that nucleates the assembly of BCL10 filaments, but the relevance of these findings for CBM complex assembly in cells remains unresolved. To uncouple cellular CARD11 recruitment of BCL10 and BCL10 filament assembly, we generated a BCL10-CARD11 fusion protein that links the C-terminus of BCL10 to the N-terminus of CARD11. When stably expressed in CARD11 KO Jurkat T cells, the BCL10-CARD11 fusion induced constitutive MALT1 activation. Furthermore, in CARD11 KO BJAB B cells, BCL10-CARD11 promoted constitutive NF-κB activation to a similar extent as CARD11 containing oncogenic driver mutations. Using structure-guided destructive mutations in the CARD11-BCL10 (CARD11 R35A) or BCL10-BCL10 (BCL10 R42E) interfaces, we demonstrate that chronic activation by the BCL10-CARD11 fusion protein was independent of the CARD11 CARD. However, activation strictly relied upon the ability of the BCL10 CARD to form oligomers. Thus, by combining distinct CARD mutations in the context of constitutively active BCL10-CARD11 fusion proteins, we provide evidence that BCL10-MALT1 recruitment to CARD11 and BCL10 oligomerization are interconnected processes, which bridge the CARD11 seed to downstream pathways in lymphocytes.
Asunto(s)
Proteína 10 de la LLC-Linfoma de Células B/inmunología , Proteínas Adaptadoras de Señalización CARD/inmunología , Guanilato Ciclasa/inmunología , Activación de Linfocitos , Multimerización de Proteína/inmunología , Proteínas Recombinantes de Fusión/inmunología , Linfocitos T/inmunología , Proteína 10 de la LLC-Linfoma de Células B/genética , Proteínas Adaptadoras de Señalización CARD/genética , Guanilato Ciclasa/genética , Células HEK293 , Humanos , Células Jurkat , Multimerización de Proteína/genética , Proteínas Recombinantes de Fusión/genética , Linfocitos T/citologíaRESUMEN
The CARD: BCL10: MALT1 (CBM) complex is an essential signaling node for maintaining both innate and adaptive immune responses. CBM complex components have gained considerable interest due to the dramatic effects of associated mutations in causing severe lymphomas, immunodeficiencies, carcinomas and inflammatory disease. While MALT1 and BCL10 are ubiquitous proteins, the CARD-containing proteins differ in their tissue expression. CARD14 is primarily expressed in keratinocytes. The CARD14-BCL10-MALT1 complex is activated by upstream pathogen-associated molecular pattern-recognition in vitro, highlighting a potentially crucial role in innate immune defense at the epidermal barrier. Recent findings have demonstrated how CARD14 orchestrates activation of the NF-κB and MAPK signaling pathways via recruitment of BCL10 and MALT1, leading to the upregulation of pro-inflammatory genes encoding IL-36γ, IL-8, Ccl20 and anti-microbial peptides. Following the identification of CARD14 gain-of function mutations as responsible for the psoriasis susceptibility locus PSORS2, the past years have witnessed a large volume of case reports and association studies describing CARD14 variants as causal or predisposing to a wide range of inflammatory skin disorders. Recent publications of mouse models also helped to better understand the physiological contribution of CARD14 to psoriasis pathogenesis. In this review, we summarize the clinical, genetic and functional aspects of human and murine CARD14 mutations and their contribution to psoriatic disease pathogenesis.
Asunto(s)
Proteínas Adaptadoras de Señalización CARD/inmunología , Heterogeneidad Genética , Guanilato Ciclasa/inmunología , Proteínas de la Membrana/inmunología , Mutación , Psoriasis/inmunología , Animales , Proteína 10 de la LLC-Linfoma de Células B/genética , Proteína 10 de la LLC-Linfoma de Células B/inmunología , Proteína 10 de la LLC-Linfoma de Células B/metabolismo , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas Adaptadoras de Señalización CARD/metabolismo , Guanilato Ciclasa/genética , Guanilato Ciclasa/metabolismo , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/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/inmunología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , Psoriasis/genética , Psoriasis/metabolismo , Transducción de Señal/genética , Transducción de Señal/inmunologíaRESUMEN
Pathogen immune responses are profoundly attenuated in fetuses and premature infants, yet the mechanisms underlying this developmental immaturity remain unclear. Here we show transcriptomic, metabolic and polysome profiling and find that monocytes isolated from infants born early in gestation display perturbations in PPAR-γ-regulated metabolic pathways, limited glycolytic capacity and reduced ribosomal activity. These metabolic changes are linked to a lack of translation of most cytokines and of MALT1 signalosome genes essential to respond to the neonatal pathogen Candida. In contrast, they have little impact on house-keeping phagocytosis functions. Transcriptome analyses further indicate a role for mTOR and its putative negative regulator DNA Damage Inducible Transcript 4-Like in regulating these metabolic constraints. Our results provide a molecular basis for the broad susceptibility to multiple pathogens in these infants, and suggest that the fetal immune system is metabolically programmed to avoid energetically costly, dispensable and potentially harmful immune responses during ontogeny.
Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Inmunidad Innata , Monocitos/inmunología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , PPAR gamma/inmunología , Factores de Transcripción/inmunología , Adulto , Proteína 10 de la LLC-Linfoma de Células B/deficiencia , Proteína 10 de la LLC-Linfoma de Células B/genética , Proteína 10 de la LLC-Linfoma de Células B/inmunología , Proteínas Adaptadoras de Señalización CARD/deficiencia , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas Adaptadoras de Señalización CARD/inmunología , Candida albicans/inmunología , Candida parapsilosis/inmunología , Humanos , Recién Nacido , Recien Nacido Prematuro , Interleucinas/deficiencia , Interleucinas/genética , Interleucinas/inmunología , Lectinas Tipo C/deficiencia , Lectinas Tipo C/genética , Lectinas Tipo C/inmunología , Lipopolisacáridos/farmacología , Análisis por Micromatrices , Monocitos/citología , Monocitos/efectos de los fármacos , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/deficiencia , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , PPAR gamma/deficiencia , PPAR gamma/genética , Cultivo Primario de Células , Biosíntesis de Proteínas/inmunología , Serina-Treonina Quinasas TOR/deficiencia , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/inmunología , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Transcriptoma/inmunología , Factor de Necrosis Tumoral alfa/deficiencia , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
The caspase recruitment domain family member 11 (CARD11 or CARMA1)-B cell CLL/lymphoma 10 (BCL10)-MALT1 paracaspase (MALT1) [CBM] signalosome complex serves as a molecular bridge between cell surface antigen receptor signaling and the activation of the NF-κB, JNK, and mTORC1 signaling axes. This positions the CBM complex as a critical regulator of lymphocyte activation, proliferation, survival, and metabolism. Inborn errors in each of the CBM components have now been linked to a diverse group of human primary immunodeficiency diseases termed "CBM-opathies." Clinical manifestations range from severe combined immunodeficiency to selective B cell lymphocytosis, atopic disease, and specific humoral defects. This surprisingly broad spectrum of phenotypes underscores the importance of "tuning" CBM signaling to preserve immune homeostasis. Here, we review the distinct clinical and immunological phenotypes associated with human CBM complex mutations and introduce new avenues for targeted therapeutic intervention.
Asunto(s)
Proteína 10 de la LLC-Linfoma de Células B/inmunología , Proteínas Adaptadoras de Señalización CARD/inmunología , Guanilato Ciclasa/inmunología , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/inmunología , Inmunodeficiencia Combinada Grave/inmunología , Transducción de Señal/inmunología , Proteína 10 de la LLC-Linfoma de Células B/genética , Proteína 10 de la LLC-Linfoma de Células B/metabolismo , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas Adaptadoras de Señalización CARD/metabolismo , Guanilato Ciclasa/genética , Guanilato Ciclasa/metabolismo , Homeostasis/genética , Homeostasis/inmunología , Humanos , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , 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 , Mutación/inmunología , Unión Proteica , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/metabolismo , Transducción de Señal/genéticaRESUMEN
The neutrophil-specific innate immune receptor CEACAM3 functions as a decoy to capture Gram-negative pathogens, such as Neisseria gonorrhoeae, that exploit CEACAM family members to adhere to the epithelium. Bacterial binding to CEACAM3 results in their efficient engulfment and triggers activation of an nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-dependent inflammatory response by human neutrophils. Herein, we report that CEACAM3 cross-linking is not sufficient for induction of cytokine production and show that the inflammatory response induced by Neisseria gonorrhoeae infection is elicited by an integration of signals from CEACAM3 and toll-like receptors. Using neutrophils from a human CEACAM-expressing mouse line (CEABAC), we use a genetic approach to reveal a molecular bifurcation of the CEACAM3-mediated antimicrobial and inflammatory responses. Ex vivo experiments with CEABAC-Rac2-/- , CEABAC-Bcl10-/- , and CEABAC-Malt1-/- neutrophils indicate that these effectors are not necessary for gonococcal engulfment, yet all 3 effectors contribute to CEACAM3-mediated cytokine production. Interestingly, although Bcl10 and Malt1 are often inextricably linked, Bcl10 enabled synergy between toll-like receptor 4 and CEACAM3, whereas Malt1 did not. Together, these findings reveal an integration of the specific innate immune receptor CEACAM3 into the network of more conventional pattern recognition receptors, providing a mechanism by which the innate immune system can unleash its response to a relentless pathogen.