Cytotoxic T-lymphocyte protein 4, also known as CTLA4 and CD152, is a single-pass type I membrane protein and a member of the immunoglobulin superfamily. It is the second member of the CD28 receptor family. The ligands or counterreceptors for these two proteins are the B7 family members, CD80 (B7-1) and CD86 (B7-2). CTLA4 transmits an inhibitory signal to T cells, whereas CD28 transmits a stimulatory signal. Intracellular CTLA4 is also found in regulatory T cells and may play an important role in their functions. CD152 or cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential receptor involved in the negative regulation of T cell activation. Because of its profound inhibitory role, CD152 has been considered a sound susceptible candidate in autoimmunity and a persuasive target for cancer immunotherapy. In particular, recent evidence suggests that CD152 is also important in the homeostasis and function of a population of suppressive cells, termed regulatory T cells (Treg).
Mouse Cytotoxic Tlymphocyte 4(CTLA-4,CD152), is a type I transmembrane T cell inhibitory molecule. mouse CTLA4 cDNA encodes 223 amino acids (aa) including a 35 aa signal sequence, a 126 aa extracellular domain (ECD) with one Ig-like V-type domain, a 21 aa transmembrane (TM) sequence, and a 41 aa cytoplasmic sequence. Within the ECD, Mouse CTLA-4 shares 68% aa sequence identity with human. CTLA4 is similar to the T cell costimulatory protein CD28 since both of the molecules bind to CD80 and CD86 on antigen-presenting cells. CTLA4 transmits an inhibitory signal to T cells, whereas CD28 transmits a stimulatory signal. Intracellular CTLA4 is also found inregulatory T cells and may play an important role in their functions. T cell activation through the T cell receptor and CD28 leads to increased expression of CTLA4. Genetic variations of CTLA4 have been associated with susceptibility to systemic lupus erythematosus(SLE), Gravesdisease(GRD), Celiac disease type3(CELIAC3) and Hepatitis B virus infection(HBVinfection).
Cathepsin B is a papain-family cysteine protease that is normally located in lysosomes, where it is involved in the turnover of proteins and plays various roles in maintaining the normal metabolism of cells. This protease has been implicated in pathological conditions, e.g., tumor progression and arthritis. In disease conditions, increases in the expression of cathepsin B occur at both the gene and protein levels. Cathepsin B is synthesized as a preproenzyme and the primary pathways for its normal trafficking to the lysosome utilize mannose 6-phosphate receptors (MPRs). Mature cathepsin B has the ability to degrade several extracellular matrix components at both neutral and acidic pH and has been implicated in the progression of several human and rodent tumors progression and arthritis. Cathepsin B expression is increased in many human cancers at the mRNA, protein and activity levels. It is also frequently overexpressed in premalignant lesions, an observation that associates this protease with an local invasive stages of cancer. Increased expression of cathepsin B in primary cancers, and especially in preneoplastic lesions, suggests that this enzyme might have pro-apoptotic features. Active cathepsin B is also secreted from tumours, a mechanism likely to be facilitated by lysosomal exocytosis or extracellular processing by surface activators. Cathepsin B is localized to caveolae on the tumour surface, where binding to the annexin II heterotetramer occurs. Thus CTSB is suggested as a tumor marker. Additionally, Cathepsin B can degrade extracellular matrix proteins, such as collagen IV and laminin, and can activate the precursor form of urokinase plasminogen activator (uPA), perhaps thereby initiating an extracellular proteolytic cascade.
Fractalkine(CX3CL1) is a single-pass type I membrane protein and belongs to the intercrine delta family. It consists of an extracellular NH2-terminal domain, a mucin-like stalk, a transmembrane α helix, and a short cytoplasmic tail. CX3CL1 exists in two forms: as a membrane-anchored or as a shed 80-95K glycoprotein. Soluble CX3CL1 is generated by limited proteolysis on the cell surface, and a disintegrin and metallopeptidase 10 (ADAM10) and ADAM17/tumor necrosis factor-α-converting enzyme (ADAM17/TACE) participate in this shedding. It has been suggested that ADAM10 acts in the constitutive shedding, and ADAM17 acts in response to cell activation. The protein may play a role in regulating leukocyte adhesion and migration processes at the endothelium.
Coxsackievirus and adenovirus receptor homolog（CAR）, also known as CXADR, is a type I transmembrane glycoprotein that belongs to the CTX family of the Ig superfamily. CXADR has monomer subunit that interacts with LNX, BAIAP1, DLG4, PRKCABP, TJP1 and CTNNB1. It also interacts with MPDZ and JAML. CXADR composed of of the epithelial apical junction complex that may function as a homophilic cell adhesion molecule and is essential for tight junction integrity. CXADR also involved in transepithelial migration of leukocytes through adhesive interactions with JAML a transmembrane protein of the plasma membrane of leukocytes. The interaction between both receptors also mediates the activation of gamma-delta T-cells, a subpopulation of T-cells residing in epithelia and involved in tissue homeostasis and repair. Upon epithelial CXADR-binding, JAML induces downstream cell signaling events in gamma-delta T-cells through PI3-kinase and MAP kinases. It results in proliferation and production of cytokines and growth factors by T-cells that in turn stimulate epithelial tissues repair.
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