Interaction between Pyrin and the Apoptotic Speck Protein (ASC) Modulates ASC-induced Apoptosis*

Patients with familial Mediterranean fever suffer sporadic inflammatory attacks characterized by fever and intense pain (in joints, abdomen, or chest). Pyrin, the product of theMEFV locus, is a cytosolic protein whose function is unknown. Using pyrin as a “bait” to probe a yeast two-hybrid library made from neutrophil cDNA, we isolatedapoptotic speck protein containing a caspase recruitment domain (CARD) (ASC), a proapoptotic protein that induces the formation of large cytosolic “specks” in transfected cells. We found that when HeLa cells are transfected with ASC, specks are formed. After co-transfection of cells with ASC plus wild type pyrin, an increase in speck-positive cells is found, and speck-positive cells show increased survival. Immunofluorescence studies show that pyrin co-localizes with ASC in specks. Speck localization requires exon 1 of pyrin, but exon 1 alone of pyrin does not result in an increase in the number of specks. Exon 1 of pyrin and exon 1 of ASC show 42% sequence similarity and resemble death domain-related structures in modeling studies. These findings link pyrin to apoptosis pathways and suggest that the modulation of cell survival may be a component of the pathophysiology of familial Mediterranean fever.

• Publication year

  2001

• Venue

  Journal of Biological Chemistry

• Publication date

  2001-10-19

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/jbc.M104730200PMID 11498534
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• Exon 1 of pyrin and exon 1 of ASC share 42% sequence similarity and resemble death domain-related structures, linking pyrin to apoptosis pathways and implicating cell-survival modulation in familial Mediterranean fever pathophysiology.

  Confidence 0.95

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewjihoonc (k5vuy3tzcm) review
• Pyrin co-localizes with ASC in specks, and this speck localization depends on exon 1 of pyrin, whereas exon 1 of pyrin alone does not increase speck formation.

  Confidence 0.97

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewjihoonc (k5vuy3tzcm) review
• ASC transfection in HeLa cells produced cytosolic specks, and co-transfection with wild-type pyrin increased the fraction of speck-positive cells and improved survival of those cells.

  Confidence 0.98

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewjihoonc (k5vuy3tzcm) review
• Using pyrin as bait in a yeast two-hybrid screen of a neutrophil cDNA library isolated ASC as an interacting protein.

  Confidence 0.98

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewjihoonc (k5vuy3tzcm) review

• apoptosis pathways

  pathway, biological process

  Cell-death-related signaling pathways discussed in relation to pyrin and ASC.

  Aliases: apoptotic pathways

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewjihoonc (k5vuy3tzcm) review
• asc

  protein, adaptor protein

  Apoptotic speck protein containing a CARD, a proapoptotic adaptor protein that forms cytosolic specks in transfected cells.

  Aliases: apoptotic speck protein containing a caspase recruitment domain, apoptotic speck protein containing a CARD

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewjihoonc (k5vuy3tzcm) review
• death domain-related structures

  protein structure, structural motif

  Protein structural motifs used as the modeling framework for comparing pyrin and ASC exon 1 regions.

  Aliases: death domain-like structures

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewjihoonc (k5vuy3tzcm) review
• exon 1 of asc

  gene region, exon

  The first exon of the ASC-encoding region compared with pyrin exon 1 for sequence and structural similarity.

  Aliases: ASC exon 1

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewjihoonc (k5vuy3tzcm) review
• exon 1 of pyrin

  gene region, exon

  The first exon of the pyrin-encoding gene region examined for its role in speck localization.

  Aliases: pyrin exon 1

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewjihoonc (k5vuy3tzcm) review
• familial mediterranean fever

  disease, condition

  An inherited autoinflammatory disease characterized by recurrent inflammatory attacks.

  Aliases: FMF

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewjihoonc (k5vuy3tzcm) review
• hela cells

  cell line

  A human cell line used for transfection experiments to observe ASC speck formation and pyrin co-expression effects.

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewjihoonc (k5vuy3tzcm) review
• pyrin

  protein

  A cytosolic protein encoded by the MEFV locus and used here as the bait protein in interaction screening.

  Aliases: MEFV product, MEFV-encoded pyrin

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewjihoonc (k5vuy3tzcm) review
• specks

  cellular structure, subcellular structure

  Large cytosolic punctate structures observed in transfected cells after ASC expression.

  Aliases: cytosolic specks

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewjihoonc (k5vuy3tzcm) review
• yeast two-hybrid library

  screening resource, library

  A neutrophil cDNA library screened for proteins that interact with pyrin in a yeast two-hybrid assay.

  Aliases: yeast two-hybrid screen, neutrophil cDNA library

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewjihoonc (k5vuy3tzcm) review

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