Cryopyrin is a member of a family of NLR proteins, which are also known as nucleotide-binding oligomerization-domain (NOD)-like receptors or CATERPILLER proteins. It is part of a cytosolic protein complex called the inflammasome that also includes ASC (apoptosis-associated speck-like protein containing a caspase-recruitment domain (CARD); also known as PYCARD, TMS1 or CARD5). The inflammasome is responsible for processing caspase-1 to its active form, which, in turn, leads to the production of mature interleukin-1β (IL-1β) — a potent pro-inflammatory cytokine — in response to bacterial, viral and other pro-inflammatory stimuli. But does cryopyrin have additional biological functions in the containment of pathogens? Macrophages that are deficient in cryopyrin are more resistant to cell death induced by certain Gram-positive bacteria, which suggests that cryopyrin participates in the initiation of necrosis, but the nature of this involvement has not been defined.
Mutations in CIAS1, the gene that encodes cryopyrin, are associated with autoinflammatory periodic-fever syndromes, which are characterized by the excessive production of IL-1β. First, the authors confirmed that the presence of the disease-associated mutations in CIAS1 resulted in necrosis-like cell death in a monocytic cell line, and then examined the mechanism by which cell death is induced. Cells that expressed the mutant cryopyrin released substantially more IL-1β than cells that expressed wild-type cryopyrin. However, cell death was shown to occur independently of caspase-1 activity and IL-1β-mediated signalling (and thus independently of inflammasome formation). Cell death induced by the mutant cryopyrin was also shown to be ASC dependent, and resulted in the release of high-mobility group box 1 (HMGB1), a protein that acts as a potent pro-inflammatory factor when released from cells that are undergoing necrosis. Similarly, excessive cell death was shown in lipopolysaccharide-challenged monocytes taken from patients with disease-associated CIAS1 mutations, by a process that was dependent on ASC and cathepsin B, resulting in the production of HMGB1.
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