The Effect of CARD19 Function on Regulating Caspase Activated Gas Proteins

Tech 2023-05-24 13:20:20 Source: Network

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preface

Cell death is a highly conserved and crucial mechanism that encompasses many highly dynamic and regulated pathways that can be manipulated and regulated by the immune system, pathogens, and therapeutic drugs.

cell death

cell deathThis includes the release of pro-inflammatory IL-1 family cytokines, detection of extracellular microbial products such as lipopolysaccharides, exogenous nucleic acids, and cellular degradation products through inherently encoded pattern recognition receptors,NFBIL-1cell deathNOD

NLRPRRNLRN

Such as cysteine activation and recruitment domains, Pyrin domains, or rod-shaped virus inhibitor repeat sequence domainsNLRASC

NODNACHTdNTPCNLRCNLR

After identifying intracellular microbial products, NLR sentinels can recruit ASC, oligomerize and assemble with pre cysteine enzyme 1 into inflammasomesASC-1IL-1ASC

NLRs

For example, NLRP1b inflammasomes are activated by direct cleavage of the N-terminal of NLRP1b by anthrax lethal factor and ubiquitination dependent activity of the Shigella flexneriE3 ligase IpaH7.8,N-terminal cleavage induces proteasome degradation, enabling the C-terminal of NLRP1b to activate cysteine enzyme 1

NLRP3 inflammasome can detect many microbial products, including extracellular ATP, pore forming toxins, potassium efflux, reactive oxygen species, lysosomal damage, uric acid, and other crystals, inducing potassium efflux stimulationCausing dissociation structures in the Golgi apparatus transport network

dTGN4NLRP3NLRP3ASCNLRP3-1In response to the production of mitochondrial ROS and the formation of inflammasomes after calcium ion flux

cell death

RCDcell deathcell deathProvides an overly simplistic perspective on RCD

A good example comes from early studies that attempted to generate caspase-8 deficient mice,These mice die of embryos due to necrosis in the developing circulating tissuesOberstRipk3-/-caspase-8caspase-8

caspase-8c-FLIPBachovchincaspase-3-7gasdermin-Dgasdermin-Dcell death

On the contrary, although caspase-8 is recruited into ASC spots containing caspase-1 and ASC, the cleaved caspase-8 is undetectable,This indicates that active inflammasomes may inhibit the activation of apoptosis

RCD

cell deathgasdermin Dcaspase-3caspase-7

caspase-1caspase-3caspase-7caspase-1caspase-7Legionella pneumophilacaspase-8NLRP3ASCIL-1caspase-1TLR2

The expression level of CARD19 is related to cell lysis of peritoneal macrophages

CARD19CARD19

To test whether CARD19 may have a broader role in regulating cell lysis in wild-type cells,We analyzed the Card19 expression level in the published transcriptome analysis data set provided by the Immune Genome project

CARD19

YpStmPBS

WtCard19-/- BMDMsWtCard19-/-Among various innate immune cells, CARD19 levels are associated with enhanced cell lysis for apoptosis and pro-inflammatory stimulation

Card19-/-129SvEvB6Card19-/-SNPCard196 MB129

cell death129SvEvCard19+/-BMDMscell deathCard19-/-B6The phenotype of Card19-/- BMDMs is unlikely to be the result of accompanying mutations at the distal site

The cleavage and activation of caspases do not require CARD19

Inflammatory necrosis is mediated by the activation of caspase-1 or caspase-11gasdermin DN-GSDMD

Surprisingly, in the case of significantly reduced cytotoxicity in Card19-/- cells, compared to B6 cells, the processing of caspase-1 after 15 minutes of infection was equivalent in both B6 and Card19-/- cells,cell death

Card19-/- BMDMsB6caspase-1 p20

This is consistent with the lower level of inflammatory necrosis of Card19-/- cells during S.Tm infectionCard19-/- BMDMscaspase-1

Similarly, the initial processing to shear p30 form of gasterminD in B6 and Card19-/- cell lysates is equivalent,The release of processed gasderminDp30 in Card19-/- cells was significantly reduced

Extracellular apoptosis is mediated by oligomerization and self processing of caspase-8caspase-8Bcl-2Bid

Similar to our findings on caspase-1, we did not find any defects in apoptotic caspases or their substrate cleavage in Card19-/- BMDMs,The same applies to the responses to Yp infection and staurosporine treatment

Card19-/- BMDMs show strong caspase-8 shear to p25 bandBidbidcaspase-3p17caspase-3poly-ADPp100GSDMEp30 N-

Card19-/-caspase-3CARD19caspase-3

In addition to these, we also observed that gas terminD cleavage to the p30N terminal band occurred under Yp infection and Sts treatmentThis is also unrelated to CARD19. In summary, these data indicate that CARD19 has a significant impact on caspase and itsActivation and cleavage of cell target proteins are not necessary

More importantly, according to the shear reactions of caspase-1 and gasdermin D under various stimulation conditions, the amount of cleaved caspase-1 and N-terminal gasdermin D released by Card19-/- cells entering the supernatant decreased, resulting in an increase in retention in cell lysates,Consistent with the results of reduced cell terminal lysis under CARD19 deficiency conditions

conclusion

CARD19caspaseStudying the function of CARD19 helps to further understand the regulatory mechanisms of cell apoptosis and thermal death

reference

1-Abu-HamadArbelCaloArzoineIsraelsonKeinan-Ben-RomanoFriedman-Shoshan-Barmatz2009
3AgliettiR.A.EstevezA.GuptaA.RamirezM.G.LiuP.S.KayagakiN.CiferriC.DixitV.M.DueberE.C.2016Caspase-11GsdmD p30Proceedings of the National Academy of Sciences of the United States of America1137858-7863
4AkhterA.GavrilinM.A.FrantzL.WashingtonS.DittyC.LimoliD.DayC.SarkarA.NewlandC.ButcharJ.2009Nlrc4/Ipafcaspase-7PLoSPLoS Pathogens5e1000361
5AnderssonU.WangH.PalmbladK.AvebergerA.C.BloomO.-Erlandsson-HarrisH.JansonA.KokkolaR.ZhangM.YangH.20001HMG-1Journal of Experimental Medicine192565-570

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