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Nlrc4

Official Full Name
NLR family, CARD domain containing 4
Background
In C. elegans, Ced4 binds and activates Ced3, an apoptotic initiator caspase, via caspase-associated recruitment domains (CARDs). Human Ced4 homologs include APAF1 (MIM 602233), NOD1/CARD4 (MIM 605980), and NOD2/CARD15 (MIM 605956). These proteins have at least 1 N-terminal CARD domain followed by a centrally located nucleotide-binding domain (NBD or NACHT) and a C-terminal regulatory domain, found only in mammals, that contains either WD40 repeats or leucine-rich repeats (LRRs). CARD12 is a member of the Ced4 family and can induce apoptosis.
Synonyms
NLRC4; NLR family, CARD domain containing 4; CARD12, caspase recruitment domain family, member 12; NLR family CARD domain-containing protein 4; CLAN; CLAN1; CLANA; CLANB; CLANC; CLAND; CLR2.1; ipaf; NOD like receptor C4; nucleotide binding oligomerizatio; nucleotide binding oligomerization domain; leucine rich repeat and CARD domain containing 4; NOD-like receptor C4; ICE-protease activating factor; ice protease-activating factor; CARD, LRR, and NACHT-containing protein; caspase recruitment domain family, member 12; caspase recruitment domain-containing protein 12; nucleotide-binding oligomerization domain, leucine rich repeat and CARD domain containing 4; CARD12

NLRC4 is also known as IPAF, NOD27, and CLR16.1. The NLRC4 protein is mainly expressed in hematopoietic tissues and cells, and includes an N-terminal CARD domain, an intermediate NBD domain, and a C-terminal LRR domain. Since it has a CARD domain, NLRC4 can directly bind to the CARD domain of pro-caspase-1, so its own activation can be independent of the presence of the adaptor protein ASC. However, studies have shown that when ASC is absent, both caspase-1 activation and IL-1β secretion are attenuated, indicating that ASC is important for the activation of NLRC4 inflammatory bodies. When the LRR domain is deleted, NLRC4 directly activates Caspase-1, suggesting that the LRR domain may play a role in inhibiting the activation of NLRC4 inflammatory bodies.

The Mechanism of NLRC4

NLRC4 inflammasome mainly plays a role in resisting external bacterial infection. When the organism is infected with bacteria such as Salmonella, Legionella, Pseudomonas, and Shigella, the assembly of NLRC4 inflammasome in macrophages plays a key role in the activation of caspase-1. Studies have shown that bacteria activate inflammatory bodies because of the presence of flagellin. The type III secretion system (T3SS) and the type IV secretion system (T4SS) are molecular needle-like structures that can inject effector proteins into the cytoplasm of host cells and play an important role in bacterial infection. Flagellin can be injected into host cells via a type III secretion system (such as Salmonella) or a type 4 secretion system (such as Legionella pneumophila) to activate NLRC4 inflammatory bodies. In order to sense the flagellin of different bacteria, the NLRC4 protein must coordinate with the member of the NLR family, NAIP (neuronal apoptosis inhibitor protein), to activate the NLRC4 inflammatory body. NAIP5 is able to sense the C-terminal region of Legionella pneumophila flagellin and activate NLRC4 inflammatory bodies, whereas Salmonella activates NLRC4 inflammatory bodies independent of NAIP5.

Nlrc4 Figure 1. NLRC4 inflammasome activation leads to diverse downstream effects. (Hafner-Bratkovi., et al. 2017)

The NLRC4 inflammatory body regulates the host immune response by regulating the secretion of IL-1β and IL-18 inflammatory factors, bacterial degradation, and Caspase-1 dependent cell apoptosis. When infected with acute Salmonella, neutrophil NLRC4 inflammatory bodies assemble and promote IL-1β secretion, but do not trigger cell sagging. After infection of the host with Legionella pneumophila, it can only replicate in specific vacuoles of macrophages. NLRC4-dependent activation of Caspase-1 promotes the binding of bacterial-containing vacuoles to lytic bodies and inhibits the replication of Legionella pneumophila. However, its inhibition of Legionella pneumophila growth is dependent on the flagellin on the surface of Legionella pneumophila and the activity of Caspase-7 in the host cell, independent of the secretion of IL-1β and IL-18.

NLRC4 and Disease

NLRC4 has an important link to human inflammatory responses. The autoinflammatory response is a systemic or organ-specific inflammatory, different from infection, tumor, or antigen-specific autoimmunity. The inflammatory response is initially seen in monogenic diseases and is characterized by spontaneous or progressively increased inflammatory activity. NLRC4-related infantile enterocolitis differs from other early onset inflammatory bowel disease (VEO-IBD). Known NLRC4-related infant Inflammatory reactions to enterocolitis extend the entire gut. If the patient survives in infancy, the final symptoms will disappear, but there is still an increase in serum IL-18 levels. The inflammatory response of the kidney is an immune response to infectious or non-infectious activators. The expression of renal tubular and interstitial NLRC4 was significantly increased in patients with diabetic nephropathy and was positively correlated with the degree of tubulointerstitial lesions. The progression of nephropathy in NLRC4-/- mice was significantly delayed. It is speculated that NLRC4 may also play an important role in kidney disease.

References:

  1. Hafner-Bratkovi, & Iva. (2017). The nlrc4 inflammasome: the pieces of the puzzle are falling into place. Inflammasome, 3(1).
  2. Kolb, R. , Phan, L. , Borcherding, N. , Liu, Y. , Yuan, F. , & Janowski, A. M. , et al. (2016). Obesity-associated nlrc4 inflammasome activation drives breast cancer progression. Nature Communications, 7, 13007.
  3. Man, S. M., & Kanneganti, T. D. (2015). Regulation of inflammasome activation. Immunological Reviews, 265(1), 6-21.

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