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A palmitoylation-depalmitoylation relay spatiotemporally controls GSDMD activation in pyroptosis

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE253306 | GEO | 2024/02/25

REPOSITORIES: GEO

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A palmitoylation-depalmitoylation relay spatiotemporally controls GSDMD activation in pyroptosis [II]

Project description:Gasdermin D (GSDMD) is the executioner of pyroptosis, which is important for host defense against pathogen infection. After activation, caspase-mediated cleavage of GSDMD liberates an N-terminal fragment (GSDMD-NT), which oligomerizes and forms pores in the plasma membrane, leading to cell death and subsequent release of proinflammatory cytokines. How this process is spatiotemporally controlled to promote pyroptosis in cells has been a fundamental, unaddressed question. Here, we identify GSDMD as a substrate for reversible S-palmitoylation on cysteine 192 (Cys192) in response to lipopolysaccharide (LPS) stimulation. We found that the palmitoyl acyltransferase DHHC7palmitoylates GSDMD to direct its cleavage by caspases in pyroptosis by promoting the interaction of GSDMD and caspases. We further show that after GSDMD cleavage, palmitoylation of GSDMD-NTpromotes its plasma membrane translocation and binding, and then acyl protein thioesterase 2 (APT2) depalmitoylates GSDMD-NT to unmask the Cys192 residue to promote oxidation-mediated oligomerization and pyroptosis. Perturbation of either palmitoylation or depalmitoylation suppresses pyroptosis, extends the survival of mice from LPS-induced lethal septic shock and sensitizes mice to bacterial infection. Thus. our findings reveal a model through which a palmitoylation-depalmitoylationrelay spatially and temporally controls GSDMD activation in pyroptosis.

2024-02-25 | GSE252911 | GEO

A palmitoylation-depalmitoylation relay spatiotemporally controls GSDMD activation in pyroptosis [I]

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A palmitoylation-depalmitoylation relay spatiotemporally controls GSDMD activation in pyroptosis

Project description:A palmitoylation-depalmitoylation relay spatiotemporally controls GSDMD activation in pyroptosis

| PRJNA1065013 | ENA

A palmitoylation-depalmitoylation relay spatiotemporally controls GSDMD activation in pyroptosis [I]

Project description:A palmitoylation-depalmitoylation relay spatiotemporally controls GSDMD activation in pyroptosis [I]

| PRJNA1063180 | ENA

A palmitoylation-depalmitoylation relay spatiotemporally controls GSDMD activation in pyroptosis [II]

Project description:A palmitoylation-depalmitoylation relay spatiotemporally controls GSDMD activation in pyroptosis [II]

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Project description:This SuperSeries is composed of the SubSeries listed below.

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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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Structure insight of GSDMD reveals the basis of GSDMD autoinhibition in cell pyroptosis.

Project description:Recent findings have revealed that the protein gasdermin D (GSDMD) plays key roles in cell pyroptosis. GSDMD binds lipids and forms pore structures to induce pyroptosis upon microbial infection and associated danger signals. However, detailed structural information for GSDMD remains unknown. Here, we report the crystal structure of the C-terminal domain of human GSDMD (GSDMD-C) at 2.64-Å resolution. The first loop on GSDMD-C inserts into the N-terminal domain (GSDMD-N), which helps stabilize the conformation of the full-length GSDMD. Substitution of this region by a short linker sequence increased levels of cell death. Mutants F283A and F283R can increase protein heterogeneity in vitro and are capable of undergoing cell pyroptosis in 293T cells. The small-angle X-ray-scattering envelope of human GSDMD is consistent with the modeled GSDMD structure and mouse GSDMA3 structure, which suggests that GSDMD adopts an autoinhibited conformation in solution. The positive potential surface of GSDMD-N covered by GSDMD-C is exposed after being released from the autoinhibition state and can form high-order oligomers via a charge-charge interaction. Furthermore, by mapping different regions of GSDMD, we determined that one short segment is sufficient to kill bacteria in vitro and can efficiently inhibit cell growth in Escherichia coli and Mycobacterium Smegmatis These findings reveal that GSDMD-C acts as an auto-inhibition executor and GSDMD-N could form pore structures via a charge-charge interaction upon cleavage by caspases during cell pyroptosis.

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