Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros

Base de dados
Ano de publicação
Tipo de documento
Intervalo de ano de publicação
1.
Small GTPases ; 10(5): 343-349, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-28650718

RESUMO

Intracellular pathogens often exploit RAB functions to establish a safe haven in which to survive and proliferate. Ehrlichia chaffeensis, an obligatory intracellular bacterium, resides in specialized membrane-bound inclusions that have early endosome-like characteristics, e.g., resident RAB5 GTPase and RAB5 effectors, including VPS34 (the catalytic subunit of class III phosphatidylinositol 3-kinase), but the inclusions lack late endosomal or lysosomal markers. Within inclusions, Ehrlichia obtains host-derived nutrients by inducing RAB5-regulated autophagy using Ehrlichia translocated factor-1 deployed by its type IV secretion system. This manipulation of RAB5 by a bacterial molecule offers a simple strategy for Ehrlichia to avoid destruction in lysosomes and obtain nutrients, membrane components, and a homeostatic intra-host-cell environment in which to grow.


Assuntos
Morte Celular Autofágica , Ehrlichia chaffeensis/fisiologia , Ehrlichiose/metabolismo , Interações Hospedeiro-Parasita/fisiologia , Sistemas de Secreção Tipo IV/metabolismo , Proteínas rab5 de Ligação ao GTP/metabolismo , Animais , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Ehrlichiose/patologia , Endossomos/metabolismo , Endossomos/microbiologia , Humanos , Lisossomos/metabolismo , Lisossomos/microbiologia
2.
Autophagy ; 12(6): 1047-8, 2016 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-27124708

RESUMO

As a central node of the macroautophagy/autophagy process, the BECN1/Beclin1-PIK3C3/VPS34 complex participates in different steps of autophagy by interacting with multiple molecules. The ATG14-associated PIK3C3 complex is involved in autophagy initiation, whereas the UVRAG-associated complex mainly modulates autophagosome maturation and endosome fusion. However, the molecular mechanism that coordinates the sequential execution of the autophagy program remains unknown. We have recently discovered that a Golgi-resident protein, PAQR3, regulates autophagy initiation as it preferentially facilitates the formation of the ATG14-linked PIK3C3 complex instead of the UVRAG-associated complex. Upon glucose starvation, AMPK directly phosphorylates T32 of PAQR3, which is crucial for the activation of the ATG14-associated class III PtdIns3K. Furthermore, Paqr3-deleted mice have a deficiency in exercise-induced autophagy as well as behavioral disorders. Thus, this work not only uncovers the regulatory mechanism of PAQR3 on autophagy initiation, but also provides a potential candidate therapeutic target for neurodegenerative diseases.


Assuntos
Proteínas Relacionadas à Autofagia/metabolismo , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Glucose/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Animais , Ativação Enzimática , Proteínas de Membrana , Camundongos Knockout , Modelos Biológicos
3.
Autophagy ; 12(11): 2145-2166, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27541856

RESUMO

Ehrlichia chaffeensis is an obligatory intracellular bacterium that causes a potentially fatal emerging zoonosis, human monocytic ehrlichiosis. E. chaffeensis has a limited capacity for biosynthesis and metabolism and thus depends mostly on host-synthesized nutrients for growth. Although the host cell cytoplasm is rich with these nutrients, as E. chaffeensis is confined within the early endosome-like membrane-bound compartment, only host nutrients that enter the compartment can be used by this bacterium. How this occurs is unknown. We found that ehrlichial replication depended on autophagy induction involving class III phosphatidylinositol 3-kinase (PtdIns3K) activity, BECN1 (Beclin 1), and ATG5 (autophagy-related 5). Ehrlichia acquired host cell preincorporated amino acids in a class III PtdIns3K-dependent manner and ehrlichial growth was enhanced by treatment with rapamycin, an autophagy inducer. Moreover, ATG5 and RAB5A/B/C were routed to ehrlichial inclusions. RAB5A/B/C siRNA knockdown, or overexpression of a RAB5-specific GTPase-activating protein or dominant-negative RAB5A inhibited ehrlichial infection, indicating the critical role of GTP-bound RAB5 during infection. Both native and ectopically expressed ehrlichial type IV secretion effector protein, Etf-1, bound RAB5 and the autophagy-initiating class III PtdIns3K complex, PIK3C3/VPS34, and BECN1, and homed to ehrlichial inclusions. Ectopically expressed Etf-1 activated class III PtdIns3K as in E. chaffeensis infection and induced autophagosome formation, cleared an aggregation-prone mutant huntingtin protein in a class III PtdIns3K-dependent manner, and enhanced ehrlichial proliferation. These data support the notion that E. chaffeensis secretes Etf-1 to induce autophagy to repurpose the host cytoplasm and capture nutrients for its growth through RAB5 and class III PtdIns3K, while avoiding autolysosomal killing.


Assuntos
Autofagia , Proteínas de Bactérias/metabolismo , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Ehrlichia chaffeensis/crescimento & desenvolvimento , Ehrlichia chaffeensis/metabolismo , Proteínas rab5 de Ligação ao GTP/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Autofagossomos/efeitos dos fármacos , Autofagossomos/metabolismo , Autofagossomos/ultraestrutura , Autofagia/efeitos dos fármacos , Proteína 5 Relacionada à Autofagia/metabolismo , Proteína Beclina-1/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Membrana Celular/ultraestrutura , Proliferação de Células/efeitos dos fármacos , Cães , Ehrlichia chaffeensis/efeitos dos fármacos , Ehrlichiose/microbiologia , Ehrlichiose/patologia , Ativação Enzimática/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Guanosina Trifosfato/metabolismo , Células HEK293 , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Proteína Huntingtina/metabolismo , Corpos de Inclusão/metabolismo , Proteínas Mutantes/metabolismo , Ligação Proteica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Ubiquitinação/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa