Cutting Edge: NLRC5-Dependent Activation of the Inflammasome

Abstract

The nucleotide-binding domain (NBD) leucine rich repeat (LRR) containing proteins, NLRs, are intracellular sensors of PAMPs and DAMPs. A subgroup of NLRs can form inflammasome complexes, which facilitate the maturation of pro-caspase-1 to caspase-1, leading to IL-1β and IL-18 cleavage and secretion. NLRC5 is predominantly expressed in hematopoetic cells and has not been studied for inflammasome function. RNAi-mediated knockdown of NLRC5 nearly eliminated caspase-1, IL-1β and IL-18 processing in response to bacterial infection, PAMPs and DAMPs. This was confirmed in primary human monocytic cells. NLRC5 together with procaspase-1, pro-IL-1β and the inflammasome adaptor, ASC, reconstituted inflammasome activity which showed cooperativity with NLPR3. The range of pathogens that activate NLRC5 inflammasome overlaps with those that activate NLRP3. Furthermore, NLRC5 biochemically associates with NLRP3 in an NBD-dependent but LRR-inhibitory fashion. These results invoke a model where NLRC5 interacts with NLRP3 to cooperatively activate the inflammasome.

NLRC5 regulates MHC class I antigen presentation in host defense against intracellular pathogens

“…To determine whether NLRC5 is involved in inflammasome activation, NLRC5 or a mutant with the LRR domain deleted, a mutation that is designed to remove the autoinhibitory effect of LRRs, was overexpressed to determine the effect on the processing of procaspase-1 and pro-IL-1β. Overexpressed NLRC5 or its deletion mutant activated this processing, and the mutant also promoted NLRP3 inflammasome activation (Sup- plementary information, Figure S5A), consistent with recent reports [16,17]. Also as reported previously [16], NLRC5 associated with NLRP3 (Supplementary information, Figure S5B), and the NACHT domain of NLRC5 mediated this association with NLRP3 (Supplementary information, Figure S5C).…”

“…Further analyses showed that the nucleotide-binding domain of NLRC5 was critical for its nuclear import and transactivation activity [15]. NLRC5 was also found to contribute to NLRP3 inflammasome activation in vitro [16]. However, one recent in vivo study did not find any role for NLRC5 [17].…”

Inflammasomes and its importance in viral infections

“…Further reports have confirmed the synergy between NLRC5 and NLRP3 in macrophage cells, demonstrating that caspase-1 activity and the subsequent processing of pro-IL-1b and pro-IL-18 in response to NLRP3-specific agonists were inhibited in the absence of NLRC5. Further, self-association of NLRC5 has also been observed to induce inflammasome activation [101].…”

Expression regulation and function of NLRC5

“…It will be interesting to know how NLRC5 exactly regulates β2M gene expression. As the known mechanism of Protein Cell & (Davis et al, 2011;Yao et al, 2012). We observed that NLRP3 mediated IL-1b production was partially impaired upon NLRC5 deficiency, but Ting's group did not find this phenotype.…”

“…While the role of NLRC5 in regulating MHC class I gene expression is well recognized by intensive studies, previous researches suggested that NLRC5 may also regulate innate immune responses through affecting TLR mediated NF-κB activation, type I interferon (IFN)-producing pathways as well as inflammasome activation (Benko et al, 2010;Cui et al, 2010;Neerincx et al, 2010;Davis et al, 2011;Lamkanfi and Kanneganti, 2012).Two studies showed NLRC5 was a positive regulator of type I IFN producing pathway in human fi broblasts and THP-1 cells (Kuenzel et al, 2010;Neerincx et al, 2010). However, NLRC5 was shown to suppress type I IFN production through association with RIG-I and MDA5 (the dsRNA sensors), or inhibit NF-κB pathway through its direct binding with IκB kinase-α (IKK-α) and IKK-β (Cui et al, 2010).…”