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

Autor: Branco LM; Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil., Amaral MP; Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil., Boekhoff H; Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.; Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany., de Lima ABF; Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil., Farias IS; Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil., Lage SL; National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, USA., Pereira GJS; Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil., Franklin BS; Institute of Innate Immunity, University Hospitals, Bonn, Germany., Bortoluci KR; Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil. kbortoluci@gmail.com.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2022 Dec 08; Vol. 13 (12), pp. 1029. Date of Electronic Publication: 2022 Dec 08.
DOI: 10.1038/s41419-022-05476-3
Abstrakt: 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-κB-mediated priming of pro-IL-1β, thus suggesting these proteases act downstream of the NAIP/NLRC4 inflammasome activation. IL-1β 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-1β secretion was abrogated in the absence of both GSDMD and cathepsins, demonstrating their non-redundant roles for the optimal IL-1β 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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