Identification of an ASC oligomerization inhibitor for the treatment of inflammatory diseases

Soriano-Teruel, Paula M. ; Garcia-Lainez, Guillermo ; Marco-Salvador, María ; Pardo, Julián (Universidad de Zaragoza) ; Arias, Maykel ; DeFord, Christian ; Merfort, I ; Vicent, María J. ; Pelegrin, Pablo ; Sancho, Mónica ; Orzaez, Mar

Resumen: The ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD)) protein is an scaffold component of different inflammasomes, intracellular multiprotein platforms of the innate immune system that are activated in response to pathogens or intracellular damage. The formation of ASC specks, initiated by different inflammasome receptors, promotes the recruitment and activation of procaspase-1, thereby triggering pyroptotic inflammatory cell death and pro-inflammatory cytokine release. Here we describe MM01 as the first-in-class small-molecule inhibitor of ASC that interferes with ASC speck formation. MM01 inhibition of ASC oligomerization prevents activation of procaspase-1 in vitro and inhibits the activation of different ASC-dependent inflammasomes in cell lines and primary cultures. Furthermore, MM01 inhibits inflammation in vivo in a mouse model of inflammasome-induced peritonitis. Overall, we highlight MM01 as a novel broad-spectrum inflammasome inhibitor for the potential treatment of multifactorial diseases involving the dysregulation of multiple inflammasomes.

Idioma: Inglés

DOI: 10.1038/s41419-021-04420-1

Año: 2021

Publicado en: CELL DEATH & DISEASE 12 (2021), [11 pp.]
ISSN: 2041-4889

Factor impacto JCR: 9.696 (2021)

Categ. JCR: CELL BIOLOGY rank: 36 / 195 = 0.185 (2021) - Q1 - T1

Factor impacto CITESCORE: 13.5 - Biochemistry, Genetics and Molecular Biology (Q1) - Immunology and Microbiology (Q1) - Neuroscience (Q1)

Factor impacto SCIMAGO: 2.099 - Cancer Research (Q1) - Medicine (miscellaneous) (Q1) - Immunology (Q1) - Cell Biology (Q1)

Financiación: info:eu-repo/grantAgreement/EC/FP7/614578/EU/Regulation of inflammatory response by extracellular ATP and P2X7 receptor signalling: through and beyond the inflammasome/Danger ATP
Financiación: info:eu-repo/grantAgreement/ES/MINECO/SAF2018-88276-R

Tipo y forma: Article (Published version)

Área (Departamento): Área Inmunología (Dpto. Microb.Ped.Radio.Sal.Pú.)