Abstract
The adaptor protein, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), connects pathogen/danger sensors such as NLRP3 and NLRC4 with caspases and is involved in inflammation and cell death. We have found that ASC activation induced caspase-8-dependent apoptosis or CA-074Me (cathepsin B inhibitor)-inhibitable necrosis depending on the cell type. Unlike necroptosis, another necrotic cell death, ASC-mediated necrosis, was neither RIP3-dependent nor necrostatin-1-inhibitable. Although acetyl-YVAD-chloromethylketone (Ac-YVAD-CMK) (caspase-1 inhibitor) did not inhibit ASC-mediated necrosis, comprehensive gene expression analyses indicated that caspase-1 expression coincided with the necrosis type. Furthermore, caspase-1 knockdown converted necrosis-type cells to apoptosis-type cells, whereas exogenous expression of either wild-type or catalytically inactive caspase-1 did the opposite. Knockdown of caspase-1, but not Ac-YVAD-CMK, suppressed the monocyte necrosis induced by Staphylococcus and Pseudomonas infection. Thus, the catalytic activity of caspase-1 is dispensable for necrosis induction. Intriguingly, a short period of caspase-1 knockdown inhibited IL-1β production but not necrosis, although longer knockdown suppressed both responses. Possible explanations of this phenomenon are discussed.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Amino Acid Chloromethyl Ketones / pharmacology
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CARD Signaling Adaptor Proteins
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Caspase 1 / genetics
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Caspase 1 / metabolism*
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Caspase 8 / genetics
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Caspase 8 / metabolism
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Caspase Inhibitors
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Cell Line, Tumor
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Cysteine Proteinase Inhibitors / pharmacology
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Cytoskeletal Proteins / biosynthesis*
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Cytoskeletal Proteins / genetics
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Dipeptides / pharmacology
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Gene Expression Regulation*
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Gene Knockdown Techniques
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Humans
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Interleukin-1beta / genetics
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Interleukin-1beta / metabolism
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NLR Family, Pyrin Domain-Containing 3 Protein
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Necrosis / genetics
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Necrosis / metabolism
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Pseudomonas Infections / genetics
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Pseudomonas Infections / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Staphylococcal Infections / genetics
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Staphylococcal Infections / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Amino Acid Chloromethyl Ketones
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CA 074 methyl ester
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CARD Signaling Adaptor Proteins
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Carrier Proteins
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Caspase Inhibitors
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Cysteine Proteinase Inhibitors
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Cytoskeletal Proteins
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Dipeptides
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IL1B protein, human
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Interleukin-1beta
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N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone
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NLR Family, Pyrin Domain-Containing 3 Protein
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NLRP3 protein, human
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NLRP4 protein, human
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PYCARD protein, human
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Repressor Proteins
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CASP8 protein, human
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Caspase 8
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Caspase 1