A Comparative Review of Pyroptosis in Mammals and Fish

Abstract

Pyroptosis is a form of programmed cell death, which is executed by gasdermin family proteins. Under the stimulation of pathogen- and/or damage-associated molecular patterns, pattern recognition receptors (PRRs) such as Nod like receptors could recruit apoptosis-associated speck-like protein containing a CARD (ASC) and pro-caspases to form inflammasomes and then activate caspases through various pathways. The activated caspases then cleave gasdermin family proteins, and N-terminal (NT) domains of gasdermins were released to form oligomeric pores, resulting in the increased membrane permeability, cell swelling, and final pyroptosis. During this process, caspases also promote the maturation and release of inflammatory cytokines such as IL-1β and IL-18, thus pyroptosis is also named inflammatory cell death. Unlike numerous gasdermin family proteins in mammals, only gasdermin E (GSDME) has been identified in fish. GSDME in fish can be cleaved by caspase-a/-b to release its NT domain and induce pyroptosis. Studies indicated that pyroptosis in fish mainly depends on NLR family pyrin domain-containing 3 (NLRP3) inflammasome. ASC and different caspase proteins also were identified in different fish species. The influences of pathogenic microorganism infection and environmental pollutants on fish pyroptosis were studied in recent years. Considering that fish living environment is affected by multiple factors such as water salinity, temperature, oxygen supply, and highly fluctuating food supply, the in-depth research about fish pyroptosis will contribute to revealing the mechanism of pyroptosis during evolution.

Keywords: caspases; fish; gasdermin E; pyroptosis.

Graphical abstract

Figure 1

The pyroptosis pathway in mammals (A) and teleost (B). (A) Pyroptosis in mammals can generally be divided into four pathways.,, In the classical pathway, PAMPs and DAMPs can be recognized by the PRRs in the cell membrane to induce NLRP3 which further activate ASC and pro-caspase-1 through PYD-PYD and CARD-CARD interaction. Activated caspase-1 can cleave GSDMD to release its NT-domain which can oligomerize to induce perforation in the cell membrane and also activate IL-1β and IL-18 which can release via the cell pore. In the non-classical pathway, caspase-4/5 (human) and −11 (mouse) can be activated after directly binding to cytoplasmic LPS. The activated caspase-4/5 and −11 can cleave GSDMD to release its NT-domain and form the micropores in cell membrane. Caspase-4/5 do not have the same ability to activate IL-1β and IL-18 as caspase-1, but caspase-11 can promote the mature of pro-IL-1β and IL-18 by NLRP3. In the caspase-3/8-mediated pathway, caspase-8 can be activated by TNF-α and other apoptotic signals to activate caspase-3, which can cleave GSDMD to release its NT-domain to form pores in cell membrane and induce pyroptosis. In the Granzyme-mediated pathway, GzmA derived from lymphocytes can cleave the Lys229/Lys244 site of GSDMB to induce cell perforation, meanwhile, GzmB released by CAR T cells can activate the caspase-3/GSDME pathway to induce pyroptosis.(B) Pyroptosis in teleost are executed by GSDME and can be divided into two ways according to the ASC-dependence or not., In the ASC-dependent pathway, the activated NLRP3 inflammasome by DAMPs or PAMPs can recruit ASC through the PYD-PYD interaction, which can further recruit caspy and then caspy2 through the CARD-CARD interaction. The activated caspy/caspy2 is responsible for the cleavage of GSDMEa/b and the mature of IL-1β. In the ASC-independent pathway, the activated NLRP3 can directly bind with caspy2 through PYD-PYD interaction, and the activated caspy2 can cleave GSDMEa/b to release its NT-domain and form pores in the cell membrane.

Figure 2

Phylogenetic trees of genes involved in pyroptosis including GSDMD and GSDME (A), caspases (B), NLRP3 (C), ASC (D) in representative teleost and mammals.