Caspase-7 activates ASM to repair gasdermin and perforin pores

Caspase-7 and acid sphingomyelinase: partner repairmans of gasdermin and perforin pores

“…Recently, a work published in Nature by Kengo Nozaki et al revealed a novel mechanism for plasma membrane pores’ repair mediated by caspase-7. 1 In this work, they found caspase-7 facilitated Intestinal epithelial cell (IEC) extrusion and repaired gasdermin D (GSDMD) and perforin pores via activating acid sphingomyelinase (ASM). The pores repair mechanism mediated by caspase-7 is independent of caspase-3 activity (Fig.…”

“…1 ). 1

Fig. 1 Caspase-7 antagonizes gasdermin D and perforin pores in inflammatory and apoptotic models and maintains cell membrane integrity by cleaving and activating acid sphingomyelinase (ASM) to produce sufficient ceramide for plasma membrane repair.

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“… 2 Caspase-3 is thought to serve as the mighty executioner of apoptosis, while caspase-7 is typically considered as a backup for caspase-3. 1 The differences in the biological functions that caspase-3 and -7 mediate are largely unknown. Currently, we only know that caspase-3 and caspase-7 show differential activities towards some substrates, including X-linked inhibitor of apoptosis (XIAP), gelsolin, BH3-interacting domain death agonist (BID), p23 and caspase-6.…”

“…1). 1 IEC extrusion plays a critical role in maintaining intestinal barrier integrity, homeostatic cell turnover, and defense against pathogens. Conventionally, caspase-3 and caspase-7 are involved in the execution step of apoptosis.…”

Gasdermin D is the only Gasdermin that provides non-redundant protection against acuteSalmonellagut infection

“…These pores mediate a lytic cell death, which releases inflammatory mediators, such as interleukin 1β (IL1β), interleukin 18 (IL18) and lipids into the extracellular milieu to alert neighboring cells (Kayagaki et al, 2015; Rauch et al, 2017; Shi et al, 2015). Gasdermins can be activated with different efficiency by the cysteine proteases Caspase-1, -3, -4, -8 and -11 and by serine proteases to execute cellular responses, thus mediating immunity against pathogens and cancer (Burgener et al, 2019; Chen et al, 2021; Hou et al, 2020; Kambara et al, 2018; Kayagaki et al, 2015; Liu et al, 2020; Orning et al, 2018; Rogers et al, 2017; Sarhan et al, 2018; Shi et al, 2015; Wang et al, 2017a; Zhang et al, 2020; Zhou et al, 2020; Nozaki et al, 2022; Zhang et al, 2022; Zhao et al, 2022; Lawrence et al, 2022). However, their individual roles, cell type specificities, and possible redundancies during oral bacterial infections, such as those caused by Salmonella enterica Serovar Typhimurium ( S .Tm), have not been comprehensively explored.…”