Mycobacterial EST12 activates a RACK1–NLRP3–gasdermin D pyroptosis–IL-1β immune pathway
| Autor: | Zi-Lu Qu, Zuoqin Luo, Xiao-Lian Zhang, Lei Yin, Yan Xie, Jian Wu, Guanghui Liu, Yidan Zhou, Yanjing Jiang, Jin Zhou |
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| Rok vydání: | 2020 |
| Předmět: |
Programmed cell death
Immunology Cell Biology Microbiology Deubiquitinating enzyme 03 medical and health sciences 0302 clinical medicine Immune system medicine Macrophage Research Articles 030304 developmental biology 0303 health sciences Multidisciplinary integumentary system Pyroptosis Receptor for activated C kinase 1 SciAdv r-articles Inflammasome biochemical phenomena metabolism and nutrition Cell biology medicine.anatomical_structure 030220 oncology & carcinogenesis biology.protein Research Article medicine.drug |
| Zdroj: | Science Advances |
| ISSN: | 2375-2548 |
| Popis: | EST12/Rv1579c activates a RACK1–NLRP3–GSDMD pyroptosis–IL-1β immune pathway to increase mycobacterial clearance. 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. |
| Databáze: | OpenAIRE |
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