Abstract
Mutations in cryopyrin and pyrin proteins are responsible for several autoinflammatory disorders in humans, suggesting that these proteins play important roles in regulating inflammation. Using a HEK293 cell-based reconstitution system that stably expresses ASC and procaspase-1 we demonstrated that neither cryopyrin nor pyrin or their corresponding disease-associated mutants could significantly activate NF-κB in this system. However, both cryopyrin and two disease-associated cryopyrin mutants induced ASC oligomerization and ASC-dependent caspase-1 activation, with the disease-associated mutants being more potent than the wild-type (WT) cryopyrin, because of increased self-oligomerization. Contrary to the proposed anti-inflammatory activity of WT pyrin, our results demonstrated that pyrin, like cryopyrin, can also assemble an inflammasome complex with ASC and procaspase-1 leading to ASC oligomerization, caspase-1 activation and interleukin-1β processing. Thus, we propose that pyrin could function as a proinflammatory molecule.
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Abbreviations
- CARD:
-
caspase-associated recruitment domain
- PYD:
-
pyrin domain
- DD:
-
death domain
- DED:
-
death effector domain
- NOD:
-
nucleotide-binding oligomerization domain
- LRR:
-
leucine-rich repeat
- NLR:
-
NACHT-LRR
- IL:
-
interleukin
- LPS:
-
lipopolysaccharide
- TNF:
-
tumor necrosis factor
- ASC:
-
apoptosis-associated speck-like protein containing a CARD
- PFS:
-
periodic fever syndromes
- FMF:
-
familial Mediterranean fever
- FCAS:
-
familial cold autoinflammatory syndrome
- FCU:
-
familial cold urticaria
- MWS:
-
Muckle-Wells syndrome
- NOMID:
-
neonatal-onset multisystem inflammatory disease
- CINCA:
-
chronic infantile neurological cutaneous and articular syndrome
- PSTPIP1:
-
proline serine threonine phosphatase-interacting protein 1
- PAPA:
-
pyogenic arthritis, pyoderma gangrenosum, and acne syndrome
- IKK:
-
IκB kinase
- PAMP:
-
pathogen-associated molecular patterns
- PGN:
-
peptidoglycans
- MDP:
-
muramyl dipeptide
- WT:
-
wildtype
- RT:
-
reverse transcription
- PCR:
-
polymerase chain reaction
- NACHT:
-
domain present in NAIP, CIITA, HET-E and TP1
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Acknowledgements
We thank Dr. Gabriel Nunez for the WT and mutant cryopyrin expression plasmids and Dr. Daniel Kastner for the WT and mutant pyrin expression plasmids. I Ibrahimi is on sabbatical leave from the University of Jordan. He is partially supported by the distinguished scholar award from the Arab fund for social and economic development. This work was supported by NIH grants AG14357 and AG13487 (to ESA).
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Yu, JW., Wu, J., Zhang, Z. et al. Cryopyrin and pyrin activate caspase-1, but not NF-κB, via ASC oligomerization. Cell Death Differ 13, 236–249 (2006). https://doi.org/10.1038/sj.cdd.4401734
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DOI: https://doi.org/10.1038/sj.cdd.4401734
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