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NLRC3 protein inhibits inflammation by disrupting NALP3 inflammasome assembly via
competition with the adaptor protein ASC for pro-caspase-1 binding
#MMPMID28584053
Eren E
; Berber M
; Özören N
J Biol Chem
2017[Jul]; 292
(30
): 12691-12701
PMID28584053
show ga
Inflammasomes are multiprotein complexes that sense pathogen-associated and
danger-associated molecular patterns and induce inflammation in cells. The NALP3
inflammasome is tightly regulated by recently discovered control mechanisms, but
other modulators still remain to be characterized. NLR family CARD-containing 3
(NLRC3) protein, a caspase recruitment domain (CARD)-containing member of the
nucleotide oligomerization domain-like receptor (NLR) family, was found to
down-regulate the NF-?B pathway and stimulator of interferon genes
(STING)-dependent cytokine secretion. However, the effect of NLRC3 on the NALP3
inflammasome or other inflammasomes is still unknown. We hypothesized that NLRC3
might inhibit NALP3 inflammasome complex assembly. Toward this end, we tested
whether NLRC3 overexpression or knockdown influences NALP3 activity in human
monocyte and HEK293FT cells when the complex is ectopically reconstituted. We
found that NLRC3 indeed decreases NALP3-induced IL-1? maturation and secretion,
pro-caspase-1 cleavage, and speck formation by apoptosis-associated speck-like
protein containing a CARD (ASC) protein in response to NALP3 activators. We also
show that endogenous NLRC3 interacts with both ASC and pro-caspase-1 but not with
NALP3, disrupts ASC speck formation through its CARD, and impairs the ASC and
pro-caspase-1 interaction. Moreover, the NLRC3 CARD alone could dampen IL-1?
secretion and ASC speck formation induced by NALP3 mutants associated with
autoinflammatory diseases. In conclusion, we show here that, besides its role in
the inhibition of the NF-?B pathway, NLRC3 interferes with the assembly and
activity of the NALP3 inflammasome complex by competing with ASC for
pro-caspase-1 binding.
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