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1.
Cell ; 184(17): 4447-4463.e20, 2021 08 19.
Artículo en Inglés | MEDLINE | ID: mdl-34363755

RESUMEN

TANK binding kinase 1 (TBK1) regulates IFN-I, NF-κB, and TNF-induced RIPK1-dependent cell death (RCD). In mice, biallelic loss of TBK1 is embryonically lethal. We discovered four humans, ages 32, 26, 7, and 8 from three unrelated consanguineous families with homozygous loss-of-function mutations in TBK1. All four patients suffer from chronic and systemic autoinflammation, but not severe viral infections. We demonstrate that TBK1 loss results in hypomorphic but sufficient IFN-I induction via RIG-I/MDA5, while the system retains near intact IL-6 induction through NF-κB. Autoinflammation is driven by TNF-induced RCD as patient-derived fibroblasts experienced higher rates of necroptosis in vitro, and CC3 was elevated in peripheral blood ex vivo. Treatment with anti-TNF dampened the baseline circulating inflammatory profile and ameliorated the clinical condition in vivo. These findings highlight the plasticity of the IFN-I response and underscore a cardinal role for TBK1 in the regulation of RCD.


Asunto(s)
Inflamación/enzimología , Proteínas Serina-Treonina Quinasas/deficiencia , Factor de Necrosis Tumoral alfa/farmacología , Células A549 , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Apoptosis , Autoinmunidad/efectos de los fármacos , Encéfalo/diagnóstico por imagen , Muerte Celular/efectos de los fármacos , Citocinas/metabolismo , Enzima Desubiquitinante CYLD/metabolismo , Femenino , Células HEK293 , Homocigoto , Humanos , Quinasa I-kappa B/metabolismo , Inmunofenotipificación , Inflamación/patología , Interferón Tipo I/metabolismo , Interferón gamma/metabolismo , Mutación con Pérdida de Función/genética , Masculino , Linaje , Fosforilación/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Receptores de Reconocimiento de Patrones/metabolismo , Receptor Toll-Like 3/metabolismo , Transcriptoma/genética , Vesiculovirus/efectos de los fármacos , Vesiculovirus/fisiología
2.
iScience ; 23(12): 101884, 2020 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-33354662

RESUMEN

We previously identified the N-quinoline-benzenesulfonamide (NQBS) scaffold as a potent inhibitor of nuclear factor-κB (NF-κB) translocation. Now, we report the structure-activity relationship of compounds with the NQBS scaffold in models of diffuse large B-cell lymphoma (DLBCL). We identified CU-O42, CU-O47, and CU-O75 as NQBS analogs with the most potent cytotoxic activity in DLBCL lines. Their anti-lymphoma effect was mediated by NF-κB sequestration to the cytoplasm of DLBCL cells. Internal Coordinates Mechanics analysis suggested direct binding between CU-O75 and IκBα/p50/p65 which leads to the stabilization of the NF-κB trimer. A whole cellular thermal shift assay confirmed direct binding of the NQBS to IκBα, an inhibitory component of the IκBα/p50/p65 trimer. Lymphoma cell line sequencing revealed CU-O75 induced downregulation of NF-κB-dependent genes and DeMAND analysis identified IκBα as one of the top protein targets for CU-O75. CU-O42 was potent in inhibiting tumor growth in two mouse models of aggressive lymphomas.

3.
Cell Death Dis ; 11(2): 94, 2020 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-32024820

RESUMEN

Adult T-cell leukemia/lymphoma (ATLL) is a malignancy of mature T cells associated with chronic infection by human T-cell lymphotropic virus type-1 (HTLV-1). ATLL patients with aggressive subtypes have dismal outcomes. We demonstrate that ATLL cells co-opt an early checkpoint within the tumor necrosis factor receptor 1 (TNFR1) pathway, resulting in survival advantage. This early checkpoint revolves around an interaction between the deubiquitinase CYLD and its target RIPK1. The status of RIPK1 K63-ubiquitination determines cell fate by creating either a prosurvival signal (ubiquitinated RIPK1) or a death signal (deubiquitinated RIPK1). In primary ATLL samples and in cell line models, an increased baseline level of CYLD phosphorylation was observed. We therefore tested the hypothesis that this modification of CYLD, which has been reported to inhibit its deubiquitinating function, leads to increased RIPK1 ubiquitination and thus provides a prosurvival signal to ATLL cells. CYLD phosphorylation can be pharmacologically reversed by IKK inhibitors, specifically by TBK1/IKKε and IKKß inhibitors (MRT67307 and TPCA). Both of the IKK sub-families can phosphorylate CYLD, and the combination of MRT67307 and TPCA have a marked effect in reducing CYLD phosphorylation and triggering cell death. ATLL cells overexpressing a kinase-inactive TBK1 (TBK1-K38A) demonstrate lower CYLD phosphorylation and subsequently reduced proliferation. IKK blockade reactivates CYLD, as evidenced by the reduction in RIPK1 ubiquitination, which leads to the association of RIPK1 with the death-inducing signaling complex (DISC) to trigger cell death. In the absence of CYLD, RIPK1 ubiquitination remains elevated following IKK blockade and it does not associate with the DISC. SMAC mimetics can similarly disrupt CYLD phosphorylation and lead to ATLL cell death through reduction of RIPK1 ubiquitination, which is CYLD dependent. These results identify CYLD as a crucial regulator of ATLL survival and point to its role as a potential novel target for pharmacologic modification in this disease.


Asunto(s)
Antineoplásicos/farmacología , Enzima Desubiquitinante CYLD/metabolismo , Quinasa I-kappa B/antagonistas & inhibidores , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Proteínas Adaptadoras de Señalización del Receptor del Dominio de Muerte/genética , Proteínas Adaptadoras de Señalización del Receptor del Dominio de Muerte/metabolismo , Enzima Desubiquitinante CYLD/genética , Regulación Leucémica de la Expresión Génica , Humanos , Quinasa I-kappa B/genética , Quinasa I-kappa B/metabolismo , Células Jurkat , Leucemia-Linfoma de Células T del Adulto/genética , Leucemia-Linfoma de Células T del Adulto/metabolismo , Leucemia-Linfoma de Células T del Adulto/patología , Fosforilación , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Transducción de Señal , Ubiquitinación
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