NLR family CARD domain-containing protein 4 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that in humans is encoded by the ''NLRC4''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

Structure

The NLRC4 protein is highly conserved across mammalian species. It bears homology to the ''C. elegans'' Ced4 protein. It contains an N-terminal

CARD Card or The Card may refer to: * Various types of plastic cards: **By type ***Magnetic stripe card *** Chip card *** Digital card **By function ***Payment card ****Credit card **** Debit card ****EC-card ****Identity card ****European Health Insur ...

domain, a central nucleotide binding/ NACHT domain, and a C-terminal leucine rich repeat ( LRR) domain. It belongs to a family of NLR proteins that includes the transcriptional co-activator

CIITA CIITA is a human gene which encodes a protein called the class II, major histocompatibility complex, transactivator. Mutations in this gene are responsible for the bare lymphocyte syndrome in which the immune system is severely compromised and c ...

and the canonical inflammasome protein

NLRP3 NLR family pyrin domain containing 3 (NLRP3) (previously known as NACHT, LRR and PYD domains-containing protein 3 ALP3and cryopyrin), is a protein that in humans is encoded by the ''NLRP3'' gene located on the long arm of chromosome 1. NLRP3 is ...

. A truncated murine NLRC4 was the first member of this family whose crystal structure was solved.

Function

NLRC4 is best associated with triggering formation of the

inflammasome Inflammasomes are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses. Activation and assembly of the inflammasome promotes proteolytic cleavage, maturation and secretion of pro-in ...

. Unlike NLRP3, certain inflammasome-dependent functions of NLRC4 may be carried out independently of the inflammasome scaffold ASC. Human Ced4 homologs include

APAF1 Apoptotic protease activating factor 1, also known as APAF1, is a human homolog of ''C. elegans'' CED-4 gene. Function The protein was identified in the lab of Xiaodong Wang as an activator of caspase-3 in the presense of cytochromeC and dATP ...

NOD1 Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is a protein receptor that in humans is encoded by the ''NOD1'' gene. It recognizes bacterial molecules and stimulates an immune reaction . NOD1 protein contains a caspase recr ...

(CARD4), and

NOD2 Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), also known as caspase recruitment domain-containing protein 15 (CARD15) or inflammatory bowel disease protein 1 (IBD1), is a protein that in humans is encoded by the ''NOD2'' g ...

(CARD15). These proteins have at least 1

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

CARD domain followed by a centrally located nucleotide-binding domain (NBD or NACHT) and a

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

regulatory domain, found only in mammals, that contains either

WD40 repeat The WD40 repeat (also known as the WD or beta-transducin repeat) is a short structural motif of approximately 40 amino acids, often terminating in a tryptophan-aspartic acid (W-D) dipeptide. Tandem copies of these repeats typically fold togethe ...

s or leucine-rich repeats (LRRs). CARD12 is a member of the Ced4 family and can induce

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

Interactions

NLRC4 has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with NAIP (there is one human NAIP but mice express at least 4 distinct NAIP proteins). The NAIP/NLRC4 interaction may determine the ligand specificity. NLRC4-dependent inflammasome activity activates

CASP1 Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosis ...

. Under certain circumstances, NLRC4 and NLRP3 may occupy the same inflammasome complex.

Clinical significance

Humans bearing activating mutations in NLRC4 can develop an

autoinflammatory Periodic fever syndromes are a set of disorders characterized by recurrent episodes of systemic and organ-specific inflammation. Unlike autoimmune disorders such as systemic lupus erythematosus, in which the disease is caused by abnormalities of ...

syndrome characterized by acute fever, hepatitis, very high serum ferritin, and other features suggestive of Macrophage Activation Syndrome (MAS). Some patients also developed a potentially life-threatening enterocolitis that abated during early childhood. In these patients, chronic and extraordinary elevation of serum IL-18 is found, in distinction from patients with NLRP3 mutations who develop Cryopyrin Associated Periodic Syndromes. A large Japanese family had much milder disease associated with cold-induced urticaria that was caused by a dominantly inherited NLRC4 mutation.

Structure

Function

Interactions

Clinical significance

References

Further reading