Abstract
Gasdermin (GSDM) family proteins were recently identified as the executioner of pyroptosis. The mechanism of pyroptosis mediated by gasdermin D (GSDMD) (a member of GSDM family) in humans and mice is well understood. In pyroptosis, mouse and human GSDMDs are cleaved by activated proinflammatory caspases (caspase-1, 4, 5, or 11) to produce anamino-terminal domain (GSDMD-NT) and a carboxyl-terminal domain (GSDMD-CT). The GSDMD-NT drives cell membrane rupture, which leads to the pyroptotic death of the cells. The expression of porcine GSDMD (pGSDMD) has recently been determined, but the activation and regulation mechanism of pGSDMD and its ability to mediate pyroptosis are largely unknown. In the present study, the activation of porcine caspase-1 (pcaspase-1) and cleavage of pGSDMD occurred in the duodenum and jejunum of a piglet challenged with enterotoxigenic Escherichia coli were first determined. Then the capability of pcaspase-1 to cleave pGSDMD was determined in a cell-free system and in human embryonic kidney cells. The pGSDMD cleavage by pcaspase-1 occurred after the pGSDMD molecule’s 276Phenylalanine-Glutamine-Serine-Aspartic acid279 motif. The pGSDMD-NT generated from the pGSDMD cleavage by pcaspase-1 showed the ability to drive cell membrane rupture in eukaryotic cells. When expressed in E. coli competent cells, pGSDMD-NT showed bactericidal activity. These results suggest that pGSDMD is a substate of pcaspase-1 and an executioner of pyroptosis. Our work sheds light on pGSDMD’s activation mechanisms and functions.
Highlights
Pyroptosis is a type of programmed cell death [1] that is characterized by cell swelling, breakdown of the plasma membrane, release of cytoplasmic contents, and vigorous inflammatory immune responses
The results show that pcaspase-1 p20 and porcine GSDMD (pGSDMD)-CT can be detected in the duodenum and jejunum of the piglet but not in the other five organs (Figure 1A)
Considering that the pcaspase-1 activation and the pGSDMD cleavage are consistent in the tissue distribution, we speculate that pcaspase-1 activation and pGSDMD cleavage are closely associated
Summary
Pyroptosis is a type of programmed cell death [1] that is characterized by cell swelling, breakdown of the plasma membrane, release of cytoplasmic contents, and vigorous inflammatory immune responses. Pyroptosis has been proven to be closely related to various human diseases, including infectious [2–4] and non-infectious diseases [5–7]. Members of gasdermin (GSDM) family have recently been proven as the executioners of pyroptosis [8–10]. Gasdermin A (GSDMA), GSDMB, GSDMC, GSDMD, GSDME ( known as deafness, autosomal dominant 5, DFNA5), and DFNB59 are the six GSDMs that have been. Porcine Caspase-1 Cleaves Gasdermin D identified in humans [11, 12]. GSDMD is the most widely studied GSDM protein in humans and mice. The amino-terminal domain of GSDMD (GSDMDNT), one of the caspase cleavage products, oligomerizes and forms pores in the plasma membrane, leading to pyroptotic cell death and thereby causes the release of proinflammatory cell components [15, 16]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
