Teleost Gasdermin E Is Cleaved by Caspase 1, 3, and 7 and Induces Pyroptosis

Abstract

Pyroptosis is a newly defined gasdermin (GSDM)-dependent inflammatory type of programmed cell death. Different from mammals, which have a panel of pyroptotic GSDM members (e.g., GSDMA-E), teleosts possess only GSDME. The pyroptotic activity and regulation mechanism of teleost GSDME remain to be elucidated. In this work, we investigated the activity of the teleost Cynoglossus semilaevis (tongue sole) GSDME (CsGSDME) in association with different caspases (CASPs). We found that CsGSDME exerted pyroptotic and bactericidal activities through its N-terminal domain. Unlike human GSDME, which is exclusively cleaved by CASP3, CsGSDME was cleaved by C. semilaevis CASP (CsCASP) 1 with high efficiency and by CsCASP3 and 7 with comparatively low efficiencies, and all cleavages occurred at the 243 FEVD 246 site in the interdomain linker region of CsGSDME. Mutation of Phe 243 to Asp/Ala and Asp 246 to Ala in 243 FEVD 246 altered the cleavage preference of CsCASP1, 3, and 7. Treatment with loss-of-function CsCASP mutants or inhibition of CsCASP activity resulted in failure of CsGSDME cleavage. CsCASP1-cleaved CsGSDME induced pyroptosis, whereas CsCASP3/7-cleaved CsGSDME and F243 mutants induced switching of cell death from apoptosis to pyroptosis. Analysis of 54 teleost GSDME sequences revealed a conserved tetrapeptide motif that fits well to the inherent cleavage site of CASP1. Taken together, the results of our study demonstrate a hitherto, to our knowledge, unrecognized GSDME cleavage mode in teleosts that is clearly different from that in mammals, thus providing an important insight into the activation mechanism of CASP-mediated, GSDM-executed pyroptosis in teleosts.

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“…Caspase-1 cleaves a 50-kD gasdermin D to a 29-kD pore forming N-terminus fragment, which is inserted into the plasma membrane causing membrane leakage and cell death by pyroptosis (Dubois et al, 2019). Recently, a role for gasdermine E in pyroptosis was implicated (Jiang et al, 2019); therefore, we will perform further studies on the role of caspase-1 and gasdermin isoforms in pyroptosis.…”

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“…It is formed by a receptor (NOD-like receptor (NLR) family or non-NLR (AIM2)), an adapter protein (ASC, apoptosis-associated specklike protein containing a CARD) and CASP1 that cleaves pro-IL18, pro-IL1β and GSDM. However, it is now clear that pyroptosis can also be activated by other caspases such as CASP3 [90] ( Figure 2). The recent description of necroptosis and pyroptosis processes has amplified the complexity of RCD understanding.…”

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“…Cas1 mRNA levels were upregulated, but it was not accompanied or followed by an upregulation of il1β mRNA levels. Cas1 upreglation could have played a role in pyroptosis, a gasdermin (GSDM)-dependent inflammatory type of programmed cell death (69). Different from mammals, which have a panel of pyroptotic GSDM members (e.g., GSDMA-E), teleosts only possess GSDME.…”

“…Different from mammals, which have a panel of pyroptotic GSDM members (e.g., GSDMA-E), teleosts only possess GSDME. Jiang et al (69) found that teleost GSDME exerted pyroptotic activity and bactericidal activities through its N-terminal domain. GSDME is specifically and highly efficiently cleaved by teleost caspase 1, releasing the N-terminal domain.…”