CD46

Official Full Name

CD46 molecule

Organism

Homo sapiens

GeneID

4179

Background

The protein encoded by this gene is a type I membrane protein and is a regulatory part of the complement system. The encoded protein has cofactor activity for inactivation of complement components C3b and C4b by serum factor I, which protects the host cell from damage by complement. In addition, the encoded protein can act as a receptor for the Edmonston strain of measles virus, human herpesvirus-6, and type IV pili of pathogenic Neisseria. Finally, the protein encoded by this gene may be involved in the fusion of the spermatozoa with the oocyte during fertilization. Mutations at this locus have been associated with susceptibility to hemolytic uremic syndrome. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2010]

Synonyms

MCP; TLX; AHUS2; MIC10; TRA2.10;

Protein Sequence

MEPPGRRECPFPSWRFPGLLLAAMVLLLYSFSDACEEPPTFEAMELIGKPKPYYEIGERVDYKCKKGYFYIPPLATHTICDRNHTWLPVSDDACYRETCPYIRDPLNGQAVPANGTYEFGYQMHFICNEGYYLIGEEILYCELKGSVAIWSGKPPICEKVLCTPPPKIKNGKHTFSEVEVFEYLDAVTYSCDPAPGPDPFSLIGESTIYCGDNSVWSRAAPECKVVKCRFPVVENGKQISGFGKKFYYKATVMFECDKGFYLDGSDTIVCDSNSTWDPPVPKCLKVLPPSSTKPPALSHSVSTSSTTKSPASSASGPRPTYKPPVSNYPGYPKPEEGILDSLDVWVIAVIVIAIVVGVAVICVVPYRYLQRRKKKGTYLTDETHREVKFTSL

Open

Disease

Multiple myeloma

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

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Detailed Information

CD46, also known as membrane cofactor protein (MCP), is a type I transmembrane protein expressed on nearly all nucleated human cells. Its main function in the immune system is its capacity to attach to complement activation pieces C3b and C4b, therefore controlling complement activation and hence maintaining immunological homeostasis. Located on chromosome 1q32 among a cluster of complement-regulating genes is the CD46 gene. Emphasizing its importance in immune modulation and complement regulation, this study investigates the many functions of CD46, its participation in immunological control, and its relationship to illnesses like atypical hemolytic uremic syndrome (aHUS).

Structure and Function of CD46

CD46 is a member of a family of complement regulating proteins and has many complement control protein (CCP) domain repetitions, which enable their interaction with complement proteins including factor I, C3b, and C4b. This structural component helps CD46 to operate as a cofactor in the proteolytic inactivation of C3b and C4b, hence regulating the complement cascade. Reducing too strong immune activation and tissue damage depends on complement control.

Apart from its cofactor action, CD46 has immunological-modulating properties. It affects T cell differentiation, especially in the production of Th1 cells and the enhancement of Treg cell development. Maintaining immunological tolerance and inhibiting autoimmune reactions depend on these actions. By affecting cytokine production—including the stimulation of IFN-γ in CD4+ T helper cells and CD8+ T cells—CD46 also influences the immunological response. Interactions with many signaling pathways and immunological molecules—including the Notch-1 ligand Jagged-1 and the serine-threonine-rich STD region of CD46, which is necessary for its recruitment to the immune synapse—carry out these regulated activities.

Figure 1 describes the cofactor activity of CD46 in the alternative pathway and its role in regulating the cleavage of C3b. Figure 1. Cofactor activity of CD46 in the alternative pathway: CD46 binds C3b on host cells, enabling factor I to cleave C3b into iC3b, preventing participation in the feedback loop. CD46 is widely expressed in human cells.( Liszewski MK, et al., 2015)

CD46 and Atypical Hemolytic Uremic Syndrome (aHUS)

Thrombotic microangiopathy (TMA) in the kidneys and other organs caused by uncontrolled activation of the alternative complement pathway defines the life-threatening disorder known as aHUS. Through both loss-of-function (LOF) and gain-of-function (GOF) processes, mutations in complement regulating proteins—including CD46—are known to predispose people to aHUS. About 10% of aHUS patients had CD46 mutations; heterozygous mutations cause susceptibility to illness and significant rates of recurrence after the first flares.

The CD46 mutations linked to aHUS span not only the extracellular domain of the protein but also intracellular signaling pathways controlling immunological and metabolic reactions in T cells. This emphasizes how complicated CD46's contribution to immune system control is. Moreover, in those with CD46 mutations, elements like inflammation, infections, and certain drugs may cause aHUS flares, indicating that outside pressures might aggravate the condition in susceptible people.

Genetics of CD46 and Its Role in Immune Regulation

Part of the RCA (complement activation) gene cluster on chromosome 1q32, the CD46 gene is Along with other complement regulating genes, this cluster comprises CD35 (CR1), CD21 (CR2), CD55 (DAF), and factor H (FH). Comprising more than 60 genes, the RCA gene cluster extends around 21.45 cM and consists of roughly 15 linked to complement control. Along with other RCA proteins, CD46 has many CCP domains that help to control complement regulation by binding factor I, C3b, and C4b. This lets CD46 be a cofactor for factor I-mediated cleavage of C3b and C4b, therefore limiting immunological damage and complement activation on self-tissues.

While its degradation-accelerating action helps restrict the length of complement activation, CD46's function as a cofactor is crucial in limiting the creation of damaging immune complexes. Though CD46 lacks the same decay-accelerating action as other RCA proteins such as CD55, its cofactor function is essential for immunological homeostasis. Its participation in T cell control emphasizes, even more, its relevance in immunological homeostasis and the prevention of diseases.

CD46 as a "Pathogen Magnet"

One of the amazing characteristics of CD46 is its targeted by many infections. Because CD46 is so widely expressed in human cells, various viruses and bacteria find a home there. Pathogens include the measles virus, adenovirus, and herpesvirus 6 as well as bacteria such as Neisseria gonorrhoeae and Streptococcus pyogenes have developed to bind to CD46 and seize control of their regulating roles. Utilizing CD46 exploitation, pathogens escape the immune system and enable infection.

For example, the adenovirus and the measles virus bind to certain CCP domains on CD46 to cause internalization and modulation of intracellular signaling. Likewise, Neisseria species target the cytoplasmic domain of CD46 to induce phosphorylation and cytoskeleton rearranging, therefore supporting bacterial adherence and invasion. These interactions draw attention to CD46's dual function as a target for pathogen control and as an immunological regulator, therefore causing immune evasion and persistent infections.

Clinical Implications and Therapeutic Interventions

Particularly in autoimmune and inflammatory illnesses, CD46 has major clinical consequences as it is crucial in immune modulation and complement control. AHUS, systemic lupus erythematosus (SLE), and common variable immunodeficiency (CVID) are only a few of the disorders that mutations in CD46 could cause. The clinical penetrance of CD46 mutations ranges; some people show inadequate penetrance and a greater risk of illness recurrence after the first episodes.

Therapeutically, the complement system seems to be a good target for conditions including aHUS. Effective in controlling aHUS and stopping disease progression, monoclonal antibodies like eculizumab, block complement C5 activation. These treatments highlight the importance of complement regulation in disease management and offer hope for individuals affected by CD46-related disorders.

References:

Liszewski MK, Atkinson JP. Complement regulator CD46: genetic variants and disease associations. Hum Genomics. 2015;9(1):7.
Fishelson Z, Kirschfink M. Complement C5b-9 and Cancer: Mechanisms of Cell Damage, Cancer Counteractions, and Approaches for Intervention. Front Immunol. 2019;10:752.

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