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

Author(s)

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

• Document type: Journal article
• Source: CELL DEATH & DISEASE; v. 13, n. 12, p. 10-pg., 2022-12-08.

Abstract

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)

• FAPESP's process: 15/09029-7 - Interaction between NLRP3 and NLRC4 inflamassomes in macrophages activation
• Grantee: Laura Migliari Branco
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 17/25942-0 - Cross talk between RIP3K and NLRP3 during T. cruzi infection
• Grantee: Karina Ramalho Bortoluci
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/21814-7 - Role of NLRP3 and lysosomal cathepsins in NLRC4 inflammasome activation
• Grantee: Laura Migliari Branco
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• FAPESP's process: 18/19252-3 - Role of NLRP3 and NAIP-NLRC4 inflammasomes after Toxoplasma gondii infection in glial cells of the central nervous system
• Grantee: Marcelo Pires Amaral
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 21/03371-6 - Impact of inflammasomes activation in central nervous system in response to ZikV e SARS-Cov2 infections
• Grantee: Karina Ramalho Bortoluci
• Support Opportunities: Regular Research Grants