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IDENTIFICATION OF A NEW COMPONENT OF THE NLRC4 INFLAMMASOME INVOLVED IN THE CLEARANCE OF SALMONELLA TYPHIMURIUM
Autores:
ANA VALERA PÉREZ
,
SYLWIA DOMINIKA TYRKALSKA
,
PABLO PELEGRIN VIVANCOS
,
ANA BELÉN PÉREZ OLIVA
,
VICTORIANO MULERO MÉNDEZ
,
Grupos de investigación:
[GI/IMIB/C060/2011] Inmunidad, inflamación y cáncer
[GI/IMIB/C003/2011] Cirugía digestiva, endocrina y trasplante de órganos abdominales
Comunicación:
Antecedentes:
The inflammasome is a cytosolic multiprotein complex that consists of three main components; a sensor protein, an adaptor protein such as ASC, and an effector cysteine-protease enzyme, usually caspase-1. In mammals, these complexes activate inflammation by IL-1?/IL-18 processing and induce a highly pyrogenic programmed cell death called pyroptosis. In this process, proteins from the GTP family such as GBP5, which has an analogue in zebrafish known as Gbp4, are also involved. Using a Salmonella enterica serovar Typhimurium (ST) infection model in zebrafish, we have identified various genes whose expression is modulated by Gbp4. One of these genes encodes a large protein of unknown functions containing several domains involved in coordinating multi-protein complex assemblies, thus being a candidate to participate in the inflammasome.
Métodos:
One-cell-stage zebrafish embryos were microinjected with different mRNAs and morfolinos combinations to analyze the effect on caspase-1 activity and survival of the larvae after ST infection. Wild type and ASC-deficient BMDM were stimulated with nigericin (NLRP3) and ST infection (NLRC4), respectively, and inflammasome assembly studied by immunofluorescence.
Resultados:
Functional studies show that the overexpression of the identified inflammasome component resulted in increased caspase-1 activity and ST resistance of zebrafish larvae. Notably, genetic studies show that it acted upstream Gbp4 and Asc. Studies in BMDM show that this protein colocalized in the speck with ASC in cells activated with ST but not nigericin.
Conclusiones:
These results suggest that identified protein is a specific component of the NLRC4 inflammsome. Studies are in progress to establish its role in inflammasome assembly and ST clearance using zebrafish, mice and human models
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