Lysosomal cathepsins act in concert with Gasdermin-D during NAIP/NLRC4-dependent IL-1 beta secretion

Autor(es)

Branco, Laura Migliari ; Amaral, Marcelo Pires ; Boekhoff, Henning ; de Lima, Ana Beatriz Figueiredo ; Farias, Ingrid Sancho ; Lage, Silvia Lucena ; Pereira, Gustavo Jose Silva ; Franklin, Bernardo Simoes ; Bortoluci, Karina Ramalho

• Tipo de documento: Artigo Científico
• Fonte: CELL DEATH & DISEASE; v. 13, n. 12, p. 10-pg., 2022-12-08.

Resumo

The NAIP/NLRC4 inflammasome is classically associated with the detection of bacterial invasion to the cytosol. However, recent studies have demonstrated that NAIP/NLRC4 is also activated in non-bacterial infections, and in sterile inflammation. Moreover, in addition to the well-established model for the detection of bacterial proteins by NAIP proteins, the participation of other cytosolic pathways in the regulation of NAIP/NLRC4-mediated responses has been reported in distinct contexts. Using pharmacological inhibition and genetic deletion, we demonstrate here that cathepsins, well known for their involvement in NLRP3 activation, also regulate NAIP/NLRC4 responses to cytosolic flagellin in murine and human macrophages. In contrast to that observed for NLRP3 agonists, cathepsins inhibition did not reduce ASC speck formation or caspase-1 maturation in response to flagellin, ruling out their participation in the effector phase of NAIP/NLRC4 activation. Moreover, cathepsins had no impact on NF-kappa B-mediated priming of pro-IL-1 beta, thus suggesting these proteases act downstream of the NAIP/NLRC4 inflammasome activation. IL-1 beta levels secreted in response to flagellin were reduced in the absence of either cathepsins or Gasdermin-D (GSDMD), a molecule involved in the induction of pyroptosis and cytokines release. Notably, IL-1 beta secretion was abrogated in the absence of both GSDMD and cathepsins, demonstrating their non-redundant roles for the optimal IL-1 beta release in response to cytosolic flagellin. Given the central role of NAIP/NLRC4 inflammasomes in controlling infection and, also, induction of inflammatory pathologies, many efforts have been made to uncover novel molecules involved in their regulation. Thus, our findings bring together a relevant contribution by describing the role of cathepsins as players in the NAIP/NLRC4-mediated responses. (AU)

• Processo FAPESP: 15/09029-7 - Interação entre os inflamassomas NLRP3 e NLRC4 na ativação de macrófagos
• Beneficiário: Laura Migliari Branco
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 17/25942-0 - Interação entre as vias mediadas por RIP3K e NLRP3 na infecção pelo Trypanosoma cruzi
• Beneficiário: Karina Ramalho Bortoluci
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 17/21814-7 - Papel de NLRP3 e catepsinas lisossomais na ativação do inflamassoma NLRC4
• Beneficiário: Laura Migliari Branco
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado Direto
• Processo FAPESP: 18/19252-3 - Papel dos inflamassomas NLRP3 e NAIP-NLRC4 na infecção por Toxoplasma gondii em células gliais do sistema nervoso central
• Beneficiário: Marcelo Pires Amaral
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 21/03371-6 - Impacto da ativação dos inflamassomas no sistema nervoso central em resposta a ZikV e SARS-Cov2
• Beneficiário: Karina Ramalho Bortoluci
• Modalidade de apoio: Auxílio à Pesquisa - Regular