4-Octyl itaconate blocks GSDMB-mediated pyroptosis and restricts inflammation by inactivating granzyme A.
Cell Prolif
; : e13711, 2024 Jul 09.
Article
de En
| MEDLINE
| ID: mdl-38982510
ABSTRACT
GSDMB-mediated pyroptosis facilitates a pro-inflammatory immune microenvironment and needs to be tightly regulated to avoid excessive inflammation. Here, we provide evidence that itaconate and its cell-permeable derivative 4-octyl itaconate (4-OI) can significantly inhibit GSDMB-rendered pyroptotic activity independent of Nrf2. 4-OI interferes proteolytic process of GSDMB by directly modifying Cys54, Cys148 and Ser212 on granzyme A (GrzA), a serine protease that site-specifically cleaves the inter-domain linker of GSDMB, instead of interaction with GSDMB, thereby blocking pyroptosis and exerts anti-inflammatory effects. Moreover, 4-OI alleviates inflammation by suppressing GSDMB-induced pyroptotic cell death during acute colitis models in intestinal epithelial GSDMB conditional transgenic mice. Our data expand the role of 4-OI as a crucial immunometabolic derivative that regulates innate immunity and inflammation through a newly identified posttranslational modification, and targeting of pyroptosis by 4-OI therefore holds potent therapeutic potential for primarily inflammatory and/or autoimmune diseases.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Langue:
En
Journal:
Cell Prolif
Année:
2024
Type de document:
Article
Pays d'affiliation:
Chine
Pays de publication:
ENGLAND
/
ESCOCIA
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GB
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GREAT BRITAIN
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INGLATERRA
/
REINO UNIDO
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SCOTLAND
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UK
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UNITED KINGDOM