title: Caspase-1 protein induces apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)-mediated necrosis independently of its catalytic activity.
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.
authors.affiliation: Division of Immunology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kakumamachi, Kanazawa, Ishikawa 920-1192, Japan.
authors.forename: Kou
authors.initials: K
authors.lastname: Motani
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kushiyama
authors.forename: Ryu
authors.initials: R
authors.lastname: Imamura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Takumi
authors.initials: T
authors.lastname: Nishiuchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Suda
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000096:biosynthesis* / Q000235:genetics; D004151:Dipeptides / Q000494:pharmacology; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009336:Necrosis / Q000235:genetics / Q000378:metabolism; D011552:Pseudomonas Infections / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013203:Staphylococcal Infections / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000590:Amino Acid Chloromethyl Ketones; C400541:CA 074 methyl ester; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D003598:Cytoskeletal Proteins; D004151:Dipeptides; C508585:IL1B protein, human; D053583:Interleukin-1beta; C098738:N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C466775:NLRP4 protein, human; C402202:PYCARD protein, human; D012097:Repressor Proteins; C505530:CASP8 protein, human; D053181:Caspase 8; D020170:Caspase 1