Bcl10-interacting CARD protein, also known as BinCARD, is a protein that in humans is encoded by the C9orf89 gene on chromosome 9. [5] [6] BinCARD is a member of the death-domain superfamily and contains a caspase recruitment domain (CARD). [7] This protein regulates apoptosis and the immune response by inhibiting Bcl10, thus implicating it in diseases stemming from Bcl10 dysfunction. [7] [8]
BinCARD, as a CARD-containing protein, is a member of the death-domain superfamily, which shares a six—helix bundle. [7] In humans, the protein has two alternatively spliced isoforms: BinCARD-1 and BinCARD-2. Both isoforms share identical sequences until residue 101, which include the CARD domain and exons 1 to 3. The longer isoform, BinCARD-1, has an extended exon 3, while the shorter BinCARD-2 has an extra transmembrane domain. [7] The conserved CARD domain has three cysteines in its native form: Cys7, Cys77, and Cys63, of which Cys7 and Cys77 form a disulfide bond and Cys63 becomes a cysteine sulfenic acid when oxidized. [7] [8]
The BinCARD protein is a member of the death-domain superfamily, which is known for regulating apoptosis and the immune response. [7] BinCARD is a negative regulator that binds to, and thus blocks the phosphorylation of, Bcl10, effectively inhibiting Bcl10 from activating the nuclear factor-κB (NF-κB). [7] [8] In particular, the BinCARD-1 isoform contains an extended C-terminal that has been observed to bind Bcl10, though it mostly localizes to the nucleus. [7] [8] The second isoform, BinCARD-2, is more abundantly expressed and localizes to both the ER and the mitochondria. This isoform is expected to contribute to apoptosis via redox processes, as its three modifiable cysteines can be oxidized by reactive oxygen species (ROS) to stimulate an innate immune response. [8]
Mutations in BinCARD and other proteins containing CARD domains are linked to Bcl10-related diseases, including lymphoma of mucosa-associated lymphoid tissue. [8] Bcl10 has been shown to induce apoptosis and to activate NF-kappaB. This protein is reported to interact with other CARD domain containing proteins including CARD9, 10, 11 and 14, which are thought to function as upstream regulators in NF-kappaB signaling. Accordingly, BinCARD protein has a pivotal role in regulating apoptotic functions.
Because of its important biological and physiological functions, apoptosis is pivotal in many clinical constituents. During normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response. [9] It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.
BinCARD has reportedly suppressed NF-kappa B activation induced by BCL10 hereby decreasing the amounts of phosphorylated Bcl10. Subsequently, mutations at the residue Leu17 or Leu65, which is highly conserved in CARD, abolished the inhibitory effects of BinCARD on both Bcl10-induced activation of NF-kappa B and phosphorylation of Bcl10. Further, expression of BinCARD inhibited Bcl10 phosphorylation induced by T cell activation signal. These results suggest that BinCARD interacts with Bcl10 to inhibit Bcl10-mediated activation of NF-kappa B and to suppress Bcl10 phosphorylation. [8] Accordingly, these processes regulating apoptosis during clinical processes such as cancer and ischemia-reperfusion injury.
BinCARD has been shown to interact with:
Fas ligand is a type-II transmembrane protein that belongs to the tumor necrosis factor (TNF) family. Its binding with its receptor induces apoptosis. Fas ligand/receptor interactions play an important role in the regulation of the immune system and the progression of cancer.
Caspase recruitment domains, or caspase activation and recruitment domains (CARDs), are interaction motifs found in a wide array of proteins, typically those involved in processes relating to inflammation and apoptosis. These domains mediate the formation of larger protein complexes via direct interactions between individual CARDs. CARD domains are found on a strikingly wide range of proteins, including helicases, kinases, mitochondrial proteins, caspases, and other cytoplasmic factors.
The death fold is a tertiary structure motif commonly found in proteins involved in apoptosis or inflammation-related processes. This motif is commonly found in domains that participate in protein–protein interactions leading to the formation of large functional complexes. Examples of death fold domains include the death domain (DD), death effector domain (DED), caspase recruitment domain (CARD), and pyrin domain (PYD).
The Fas receptor, also known as Fas, FasR, apoptosis antigen 1, cluster of differentiation 95 (CD95) or tumor necrosis factor receptor superfamily member 6 (TNFRSF6), is a protein that in humans is encoded by the FAS gene. Fas was first identified using a monoclonal antibody generated by immunizing mice with the FS-7 cell line. Thus, the name Fas is derived from FS-7-associated surface antigen.
The BH3 interacting-domain death agonist, or BID, gene is a pro-apoptotic member of the Bcl-2 protein family. Bcl-2 family members share one or more of the four characteristic domains of homology entitled the Bcl-2 homology (BH) domains, and can form hetero- or homodimers. Bcl-2 proteins act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities.
The BCL2 associated agonist of cell death (BAD) protein is a pro-apoptotic member of the Bcl-2 gene family which is involved in initiating apoptosis. BAD is a member of the BH3-only family, a subfamily of the Bcl-2 family. It does not contain a C-terminal transmembrane domain for outer mitochondrial membrane and nuclear envelope targeting, unlike most other members of the Bcl-2 family. After activation, it is able to form a heterodimer with anti-apoptotic proteins and prevent them from stopping apoptosis.
Caspase-9 is an enzyme that in humans is encoded by the CASP9 gene. It is an initiator caspase, critical to the apoptotic pathway found in many tissues. Caspase-9 homologs have been identified in all mammals for which they are known to exist, such as Mus musculus and Pan troglodytes.
Caspase-8 is a caspase protein, encoded by the CASP8 gene. It most likely acts upon caspase-3. CASP8 orthologs have been identified in numerous mammals for which complete genome data are available. These unique orthologs are also present in birds.
CD27 is a member of the tumor necrosis factor receptor superfamily. It is currently of interest to immunologists as a co-stimulatory immune checkpoint molecule, and is the target of an anti-cancer drug in clinical trials.
Death receptor 4 (DR4), also known as TRAIL receptor 1 (TRAILR1) and tumor necrosis factor receptor superfamily member 10A (TNFRSF10A), is a cell surface receptor of the TNF-receptor superfamily that binds TRAIL and mediates apoptosis.
Bcl-2-like protein 11, commonly called BIM, is a protein that in humans is encoded by the BCL2L11 gene.
B-cell lymphoma/leukemia 10 is a protein that in humans is encoded by the BCL10 gene. Like BCL2, BCL3, BCL5, BCL6, BCL7A, and BCL9, it has clinical significance in lymphoma.
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions in a variety of cellular pathways related to both cell survival and death. In terms of cell death, RIPK1 plays a role in apoptosis and necroptosis. Some of the cell survival pathways RIPK1 participates in include NF-κB, Akt, and JNK.
PYCARD, often referred to as ASC, is a protein that in humans is encoded by the PYCARD gene. It is localized mainly in the nucleus of monocytes and macrophages. In case of pathogen infection, however, it relocalizes rapidly to the cytoplasm, perinuclear space, endoplasmic reticulum and mitochondria and it is a key adaptor protein in activation of the inflammasome.
Bcl-2-related protein A1 is a protein that in humans is encoded by the BCL2A1 gene.
Caspase recruitment domain-containing protein 11 also known as CARD-containing MAGUK protein 1 is a protein in the CARD-CC protein family that in humans is encoded by the CARD11 gene.
Apoptosis regulatory protein Siva is a protein that in humans is encoded by the SIVA1 gene. This gene encodes a protein with an important role in the apoptotic pathway induced by the CD27 antigen, a member of the tumor necrosis factor receptor (TFNR) superfamily. The CD27 antigen cytoplasmic tail binds to the N-terminus of this protein. Two alternatively spliced transcript variants encoding distinct proteins have been described.
Bcl-2-modifying factor is a protein that in humans is encoded by the BMF gene.
Caspase recruitment domain-containing protein 10 is a protein in the CARD-CC protein family that in humans is encoded by the CARD10 gene.
Caspase recruitment domain-containing protein 14, also known as CARD-containing MAGUK protein 2, is a protein in the CARD-CC protein family that in humans is encoded by the CARD14 gene.
