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Mycobacterial EST12 activates a RACK1–NLRP3–gasdermin D pyroptosis–IL-1β immune pathway

Pyroptosis, an inflammatory form of programmed cell death, has been implicated in eliminating pathogenic infections. However, macrophage pyroptosis–related proteins from Mycobacterium tuberculosis (M.tb) have largely gone unexplored. Here, we identified a cell pyroptosis–inducing protein, Rv1579c, n...

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Autores principales: Qu, Zilu, Zhou, Jin, Zhou, Yidan, Xie, Yan, Jiang, Yanjing, Wu, Jian, Luo, Zuoqin, Liu, Guanghui, Yin, Lei, Zhang, Xiao-Lian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608829/
https://www.ncbi.nlm.nih.gov/pubmed/33097533
http://dx.doi.org/10.1126/sciadv.aba4733
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author Qu, Zilu
Zhou, Jin
Zhou, Yidan
Xie, Yan
Jiang, Yanjing
Wu, Jian
Luo, Zuoqin
Liu, Guanghui
Yin, Lei
Zhang, Xiao-Lian
author_facet Qu, Zilu
Zhou, Jin
Zhou, Yidan
Xie, Yan
Jiang, Yanjing
Wu, Jian
Luo, Zuoqin
Liu, Guanghui
Yin, Lei
Zhang, Xiao-Lian
author_sort Qu, Zilu
collection PubMed
description Pyroptosis, an inflammatory form of programmed cell death, has been implicated in eliminating pathogenic infections. However, macrophage pyroptosis–related proteins from Mycobacterium tuberculosis (M.tb) have largely gone unexplored. Here, we identified a cell pyroptosis–inducing protein, Rv1579c, named EST12, secreted from the M.tb H37Rv region of difference 3. EST12 binds to the receptor for activated C kinase 1 (RACK1) in macrophages, and the EST12-RACK1 complex recruits the deubiquitinase UCHL5 to promote the K48-linked deubiquitination of NLRP3, subsequently leading to an NLRP3 inflammasome caspase-1/11–pyroptosis gasdermin D–interleukin-1β immune process. Analysis of the crystal structure of EST12 reveals that the amino acid Y80 acts as a critical binding site for RACK1. An EST12-deficient strain (H37RvΔEST12) displayed higher susceptibility to M.tb infection in vitro and in vivo. These results provide the first proof that RACK1 acts as an endogenous host sensor for pathogens and that EST12-RACK1–induced pyroptosis plays a pivotal role in M.tb-induced immunity.
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spelling pubmed-76088292020-11-13 Mycobacterial EST12 activates a RACK1–NLRP3–gasdermin D pyroptosis–IL-1β immune pathway Qu, Zilu Zhou, Jin Zhou, Yidan Xie, Yan Jiang, Yanjing Wu, Jian Luo, Zuoqin Liu, Guanghui Yin, Lei Zhang, Xiao-Lian Sci Adv Research Articles Pyroptosis, an inflammatory form of programmed cell death, has been implicated in eliminating pathogenic infections. However, macrophage pyroptosis–related proteins from Mycobacterium tuberculosis (M.tb) have largely gone unexplored. Here, we identified a cell pyroptosis–inducing protein, Rv1579c, named EST12, secreted from the M.tb H37Rv region of difference 3. EST12 binds to the receptor for activated C kinase 1 (RACK1) in macrophages, and the EST12-RACK1 complex recruits the deubiquitinase UCHL5 to promote the K48-linked deubiquitination of NLRP3, subsequently leading to an NLRP3 inflammasome caspase-1/11–pyroptosis gasdermin D–interleukin-1β immune process. Analysis of the crystal structure of EST12 reveals that the amino acid Y80 acts as a critical binding site for RACK1. An EST12-deficient strain (H37RvΔEST12) displayed higher susceptibility to M.tb infection in vitro and in vivo. These results provide the first proof that RACK1 acts as an endogenous host sensor for pathogens and that EST12-RACK1–induced pyroptosis plays a pivotal role in M.tb-induced immunity. American Association for the Advancement of Science 2020-10-23 /pmc/articles/PMC7608829/ /pubmed/33097533 http://dx.doi.org/10.1126/sciadv.aba4733 Text en Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/ https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Research Articles
Qu, Zilu
Zhou, Jin
Zhou, Yidan
Xie, Yan
Jiang, Yanjing
Wu, Jian
Luo, Zuoqin
Liu, Guanghui
Yin, Lei
Zhang, Xiao-Lian
Mycobacterial EST12 activates a RACK1–NLRP3–gasdermin D pyroptosis–IL-1β immune pathway
title Mycobacterial EST12 activates a RACK1–NLRP3–gasdermin D pyroptosis–IL-1β immune pathway
title_full Mycobacterial EST12 activates a RACK1–NLRP3–gasdermin D pyroptosis–IL-1β immune pathway
title_fullStr Mycobacterial EST12 activates a RACK1–NLRP3–gasdermin D pyroptosis–IL-1β immune pathway
title_full_unstemmed Mycobacterial EST12 activates a RACK1–NLRP3–gasdermin D pyroptosis–IL-1β immune pathway
title_short Mycobacterial EST12 activates a RACK1–NLRP3–gasdermin D pyroptosis–IL-1β immune pathway
title_sort mycobacterial est12 activates a rack1–nlrp3–gasdermin d pyroptosis–il-1β immune pathway
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608829/
https://www.ncbi.nlm.nih.gov/pubmed/33097533
http://dx.doi.org/10.1126/sciadv.aba4733
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