Succination inactivates gasdermin D and blocks pyroptosis

Abstract

Activated macrophages undergo a metabolic switch to aerobic glycolysis accumulating Krebs cycle intermediates that alter transcription of immune response genes. Here we extend these observations by defining fumarate as an inhibitor of pyroptotic cell death. We found that dimethyl fumarate (DMF) delivered to cells or endogenous fumarate reacts with gasdermin D (GSDMD) at critical cysteine residues to form S-(2-succinyl)-cysteine. GSDMD succination prevents its interaction with caspases, limiting its processing, oligomerization, and capacity to induce cell death. In mice, the administration of DMF protects against LPS shock and alleviates familial Mediterranean fever and experimental autoimmune encephalitis (EAE) by targeting GSDMD. Collectively, these findings identify GSDMD as a target of fumarate and reveal a mechanism of action for fumarate-based therapeutics including DMF used to treat multiple sclerosis.

Activation of GSDME compensates for GSDMD deficiency in a mouse model of NLRP3 inflammasomopathy

“…Although young NOMID mice lacking the IL-1 receptor do not develop inflammation 52 , a persistent low-grade inflammation is reported in FCAS mice and MWS mice with defective IL-1 and IL-18 signaling 53 , suggesting that pyroptosis may be the culprit. In support of this view, knocking out GSDMD prevents the pathogenesis of NOMID 54 , Familial Mediterranean Fever (FMF) 55 , and experimental autoimmune encephalitis 56 . However, how these mutant mice with an underlying dysregulated NLRP3 inflammasome activity withstand superimposed inflammatory challenges has not been studied.…”

Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses

“…Fumarate is formed in the TCA cycle by the SDH-catalyzed dehydrogenation of succinate [98,111,156,158]. Activation of innate immune cells, such as macrophages and monocytes, with pro-inflammatory stimuli (e.g., LPS, IFN-γ) leads to remodeling of the TCA cycle and intracellular accumulation of fumarate [28,39,118,[159][160][161]. LPS-activated macrophages show a substantial increase in flux through the induction of aspartate-arginosuccinate shunt, which fuels and maintains the TCA cycle flux [45,160].…”

“…The elevated cytokine response in these cells is linked to an increase in the amount of fumarate sufficient to drive the response by activating HIF-1α [33,162]. The accumulation of fumarate by inhibiting fumarate hydratase (FH; also known as fumarase) with FHIN1 impairs cell death and reduces the formation of gasdermin D, the executioner of pyroptosis [159]. An in vivo-compatible FH inhibitor, FHIN2, elevates FH levels in vivo and reduces IL-1β, indicating that fumarate inhibits pyroptosis in vivo [159].…”

“…The accumulation of fumarate by inhibiting fumarate hydratase (FH; also known as fumarase) with FHIN1 impairs cell death and reduces the formation of gasdermin D, the executioner of pyroptosis [159]. An in vivo-compatible FH inhibitor, FHIN2, elevates FH levels in vivo and reduces IL-1β, indicating that fumarate inhibits pyroptosis in vivo [159]. Loss of function of FH in cancers increases fumarate levels leading to elevated accumulation of NRF2 [163,164].…”

“…Through modification of the active site cysteine (Cys152 in humans) and resulting in inactivation of GAPDH, DMF has been proposed to downregulate glycolysis and ultimately mediate its anti-inflammatory effects observed in B lymphocytes of DMF-treated multiple sclerosis patients. However, a recent study suggested that this mechanism does not have the primary role in DMF-mediated immunosuppression [159].…”