A unique bacterial tactic to circumvent the cell death crosstalk induced by blockade of caspase‐8

Abstract

Upon invasive bacterial infection of colonic epithelium, host cells induce several types of cell death to eliminate pathogens. For instance, necroptosis is a RIPK‐dependent lytic cell death that serves as a backup system to fully eliminate intracellular pathogens when apoptosis is inhibited; this phenomenon has been termed “cell death crosstalk”. To maintain their replicative niche and multiply within cells, some enteric pathogens prevent epithelial cell death by delivering effectors via the type III secretion system. In this study, we found that Shigella hijacks host cell death crosstalk via a dual mechanism: inhibition of apoptosis by the OspC1 effector and inhibition of necroptosis by the OspD3 effector. Upon infection by Shigella, host cells recognize blockade of caspase‐8 apoptosis signaling by OspC1 effector as a key danger signal and trigger necroptosis as a backup form of host defense. To counteract this backup defense, Shigella delivers the OspD3 effector, a protease, to degrade RIPK1 and RIPK3, preventing necroptosis. We believe that blockade of host cell death crosstalk by Shigella is a unique intracellular survival tactic for prolonging the bacterium's replicative niche.

From pyroptosis, apoptosis and necroptosis to PANoptosis: A mechanistic compendium of programmed cell death pathways

“…Growing evidence has shown an interplay between PCD pathways and microbial factors, suggesting that these pathways may have played important roles during mammalian co-evolution with microbes [142] , [143] . Many pathogens carry microbial effectors that can actively enhance cell viability by blocking PCD pathways or by activating proliferation pathways [144] , [145] . It is likely that host cells have developed complex regulation and interconnection of cell death pathways to overcome the challenges presented by such microbial effectors.…”

NleB2 from enteropathogenic Escherichia coli is a novel arginine-glucose transferase effector

“…Characterization of the activity of bacterial effector proteins has revealed new classes of enzymes as well as unique post-translational protein modifications. For example, EspL from EPEC and OspD3 from Shigella are members of a novel family of cysteine protease effectors that can block necroptotic cell death by cleaving and inactivating the RHIM-containing proteins, RIPK1 and RIPK3 [30,31]. NleE from EPEC and OspZ from Shigella are S-adenosyl-Lmethionine (SAM)-dependent methyltransferases that modify a cysteine residue in the zinc finger domains of TAB2 and TAB3, thereby preventing their interaction with ubiquitinated TRAF proteins and leading to inhibition of NF-κB activation [20,[32][33][34].…”

Manipulation of epithelial cell death pathways by Shigella

“…Prior work showed that during early infection of epithelial cells, Shigella uses the T3SS effector OspC3 to prevent caspase‐4‐dependent pyroptotic death (Kobayashi et al , ). Ashida et al () have now demonstrated the T3SS‐dependent inhibition of the interconnected caspase‐8 and necroptotic pathways.…”

“…By screening mutant strains of S. flexneri that lack T3SS‐secreted effectors in HT29 human colon epithelial cells, Ashida et al () identified OspD3 as an inhibitor of necroptosis. Further analysis showed that OspD3 is a protease that cleaves within the RHIM domain of essential necroptotic factors RIPK1 and RIPK3, targeting them for degradation.…”

“…The mechanisms of caspase‐8 activation and its inhibition by OspC1 during Shigella infection remain unknown. OspC1 is not related to known T3SS effectors from other pathogens (Ashida et al , ). Enteropathogenic Escherichia coli (EPEC) and enterohaemorrhagic E. coli (EHEC) inhibit apoptosis through NleF that inhibits the activity of caspase‐8 and caspase‐3 and NleB that blocks recruitment of pro‐caspase‐8 by FADD as well as disrupting TNF‐induced necroptosis (Li et al , ; Pollock et al , ).…”