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1.
J Exp Med ; 214(7): 1949-1972, 2017 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-28606988

RESUMO

MDA5 is a cytosolic sensor of double-stranded RNA (ds)RNA including viral byproducts and intermediates. We studied a child with life-threatening, recurrent respiratory tract infections, caused by viruses including human rhinovirus (HRV), influenza virus, and respiratory syncytial virus (RSV). We identified in her a homozygous missense mutation in IFIH1 that encodes MDA5. Mutant MDA5 was expressed but did not recognize the synthetic MDA5 agonist/(ds)RNA mimic polyinosinic-polycytidylic acid. When overexpressed, mutant MDA5 failed to drive luciferase activity from the IFNB1 promoter or promoters containing ISRE or NF-κB sequence motifs. In respiratory epithelial cells or fibroblasts, wild-type but not knockdown of MDA5 restricted HRV infection while increasing IFN-stimulated gene expression and IFN-ß/λ. However, wild-type MDA5 did not restrict influenza virus or RSV replication. Moreover, nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV. Thus, human MDA5 deficiency is a novel inborn error of innate and/or intrinsic immunity that causes impaired (ds)RNA sensing, reduced IFN induction, and susceptibility to the common cold virus.


Assuntos
Helicase IFIH1 Induzida por Interferon/genética , Mutação , Infecções por Picornaviridae/genética , Infecções por Picornaviridae/virologia , Rhinovirus/fisiologia , Antivirais/farmacologia , Sequência de Bases , Células Cultivadas , Pré-Escolar , Análise Mutacional de DNA/métodos , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/virologia , Expressão Gênica/efeitos dos fármacos , Genes Recessivos/genética , Heterozigoto , Homozigoto , Interações Hospedeiro-Patógeno , Humanos , Helicase IFIH1 Induzida por Interferon/deficiência , Interferons/farmacologia , Masculino , Linhagem
2.
Cell ; 159(7): 1578-90, 2014 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-25525876

RESUMO

Proteasomes and lysosomes constitute the major cellular systems that catabolize proteins to recycle free amino acids for energy and new protein synthesis. Tripeptidyl peptidase II (TPPII) is a large cytosolic proteolytic complex that functions in tandem with the proteasome-ubiquitin protein degradation pathway. We found that autosomal recessive TPP2 mutations cause recurrent infections, autoimmunity, and neurodevelopmental delay in humans. We show that a major function of TPPII in mammalian cells is to maintain amino acid levels and that TPPII-deficient cells compensate by increasing lysosome number and proteolytic activity. However, the overabundant lysosomes derange cellular metabolism by consuming the key glycolytic enzyme hexokinase-2 through chaperone-mediated autophagy. This reduces glycolysis and impairs the production of effector cytokines, including IFN-γ and IL-1ß. Thus, TPPII controls the balance between intracellular amino acid availability, lysosome number, and glycolysis, which is vital for adaptive and innate immunity and neurodevelopmental health.


Assuntos
Imunidade Adaptativa , Aminopeptidases/metabolismo , Dipeptidil Peptidases e Tripeptidil Peptidases/metabolismo , Glicólise , Imunidade Inata , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/metabolismo , Proteólise , Serina Endopeptidases/metabolismo , Sequência de Aminoácidos , Aminopeptidases/química , Animais , Dipeptidil Peptidases e Tripeptidil Peptidases/química , Feminino , Humanos , Síndromes de Imunodeficiência/imunologia , Lisossomos/metabolismo , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Linhagem , Alinhamento de Sequência , Serina Endopeptidases/química
3.
J Exp Med ; 211(13): 2549-66, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25422492

RESUMO

DOCK8 mutations result in an inherited combined immunodeficiency characterized by increased susceptibility to skin and other infections. We show that when DOCK8-deficient T and NK cells migrate through confined spaces, they develop cell shape and nuclear deformation abnormalities that do not impair chemotaxis but contribute to a distinct form of catastrophic cell death we term cytothripsis. Such defects arise during lymphocyte migration in collagen-dense tissues when DOCK8, through CDC42 and p21-activated kinase (PAK), is unavailable to coordinate cytoskeletal structures. Cytothripsis of DOCK8-deficient cells prevents the generation of long-lived skin-resident memory CD8 T cells, which in turn impairs control of herpesvirus skin infections. Our results establish that DOCK8-regulated shape integrity of lymphocytes prevents cytothripsis and promotes antiviral immunity in the skin.


Assuntos
Forma Celular/imunologia , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Imunidade , Células Matadoras Naturais/patologia , Pele/imunologia , Pele/virologia , Linfócitos T/patologia , Animais , Apoptose/efeitos dos fármacos , Bovinos , Adesão Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/patologia , Forma Celular/efeitos dos fármacos , Quimiocina CXCL12/farmacologia , Quimiotaxia/efeitos dos fármacos , Colágeno/farmacologia , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Feminino , Fatores de Troca do Nucleotídeo Guanina/deficiência , Humanos , Imunidade/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/patologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Proteína cdc42 de Ligação ao GTP/metabolismo , Quinases Ativadas por p21/metabolismo
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