CD46 - CD46 molecule |Elisa - Clia - Antibody - Protein

Background

CD46, also known as membrane cofactor protein (MCP), is a transmembrane glycoprotein that serves primarily as a regulatory component of the complement system, protecting host cells from complement-mediated damage. CD46 is widely expressed on almost all nucleated cells and plays a key role in immune regulation, ensuring that the complement system, which is responsible for clearing pathogens, does not attack the body’s own cells. CD46 does this by serving as a cofactor for the proteolytic cleavage of C3b and C4b, two crucial components of the complement pathway, which are inactivated by factor I.

In addition to its role in the complement system, CD46 is involved in various immune functions, including modulation of T-cell responses, immune tolerance, and viral entry. Several viruses, such as the measles virus and human herpesvirus 6 (HHV-6), use CD46 as a receptor to gain entry into host cells, highlighting its involvement in viral pathogenesis. CD46 also has a role in reproductive biology, being expressed on spermatozoa and participating in the process of fertilization.

Protein Structure

The CD46 molecule is a type I transmembrane glycoprotein that is composed of several distinct structural domains:

Extracellular Domain:

• The extracellular region of CD46 consists of four complement control protein (CCP) domains. These domains are responsible for the interaction of CD46 with components of the complement system, such as C3b and C4b.
• The CCP domains have a high affinity for factor I, a serine protease that inactivates C3b and C4b by cleaving them, thereby preventing the formation of the complement membrane attack complex (MAC) on host cells.
• In addition to its interaction with complement proteins, the extracellular domain of CD46 is involved in the binding of viral ligands, such as the measles virus and HHV-6, facilitating their entry into the host cells.

O-Glycosylation and N-Glycosylation Sites:

• CD46 contains multiple glycosylation sites that play a role in its function and stability. These modifications help maintain the structural integrity of the protein, protect it from proteolysis, and modulate its interactions with ligands.
• O-glycosylation is particularly prominent on CD46 and is crucial for proper receptor function, especially in immune responses and viral entry.

Transmembrane Domain:

• CD46 is anchored in the cell membrane through a single-pass transmembrane domain. This domain plays a structural role, ensuring that the extracellular CCP domains are correctly oriented for ligand binding and interaction with the complement system.
• The transmembrane region also participates in receptor signaling by acting as a scaffold for downstream signaling molecules.

Cytoplasmic Tail:

• CD46 has two main isoforms based on its cytoplasmic tail: CYT-1 and CYT-2. These tails are involved in transmitting intracellular signals upon receptor activation and interaction with other signaling proteins.
• The cytoplasmic tails interact with molecules involved in T-cell activation and regulation of adaptive immune responses. CD46 signaling can promote regulatory T cell (Treg) differentiation, leading to immune tolerance, or Th1 responses, which are involved in pathogen clearance.

Classification and Subtypes

CD46 exists in several isoforms, which are generated through alternative splicing of the CD46 gene. The most well-characterized isoforms differ primarily in the length and sequence of their cytoplasmic tails:

CD46-CYT1 Isoform:

• This isoform contains the CYT1 cytoplasmic tail, which is involved in transmitting specific signaling pathways that are linked to T-cell activation and Th1 immune responses.

CD46-CYT2 Isoform:

• The CYT2 isoform has a shorter cytoplasmic tail than CYT1 and is associated with different signaling cascades. CYT2 is more commonly involved in immunoregulation and the induction of regulatory T cells (Tregs), promoting immune tolerance.

In addition to these isoforms, CD46 is subject to post-translational modifications, including glycosylation, that can alter its function and localization.

Function and Biological Significance

CD46 serves as a multifaceted protein involved in immune regulation, complement protection, and pathogen entry. Its primary functions include:

Complement Regulation:

• CD46 is a complement regulatory protein that ensures the complement system is activated against pathogens but not the host's own cells. It acts as a cofactor for the proteolytic cleavage of C3b and C4b by factor I, rendering them inactive and preventing further activation of the complement cascade.
• By regulating complement activation, CD46 protects cells from complement-mediated lysis, which could otherwise lead to autoimmune damage or excessive inflammation.

Immune Regulation:

• CD46 plays a key role in the modulation of T-cell responses. Upon interaction with T cells, CD46 can promote Th1 immune responses, which are important for combating intracellular pathogens like viruses and bacteria.
• In contrast, under certain conditions, CD46 can induce the differentiation of regulatory T cells (Tregs), promoting immune tolerance and preventing autoimmune diseases. This dual function in both immune activation and regulation positions CD46 as a crucial immune checkpoint molecule.

Viral Receptor:

• Several viruses, including the measles virus, adenoviruses, and human herpesvirus 6 (HHV-6), use CD46 as a receptor for cell entry. CD46 facilitates viral attachment and entry into host cells, making it a key player in viral pathogenesis.
• Viral binding to CD46 can modulate its immune functions, potentially aiding viral evasion of the immune system.

Fertility and Reproduction:

• CD46 is expressed on spermatozoa and is involved in the process of fertilization. It is thought to play a role in the fusion of sperm with the egg during fertilization, contributing to successful conception.

Immune Privilege and Transplantation:

• CD46 is highly expressed in immune-privileged tissues, such as the eye and testis, where it helps prevent inappropriate immune responses that could damage sensitive tissues. It has also been investigated as a potential target for promoting immune tolerance in transplantation, as its ability to induce regulatory T cells could reduce the risk of graft rejection.

Clinical Issues

The dysregulation or mutation of CD46 has been associated with several diseases, including:

Atypical Hemolytic Uremic Syndrome (aHUS):

• Mutations in the CD46 gene can lead to atypical hemolytic uremic syndrome (aHUS), a rare disorder characterized by complement-mediated destruction of red blood cells, kidney failure, and thrombosis. In aHUS, defective CD46 fails to regulate complement activation, leading to excessive complement activity and tissue damage.
• Genetic testing for CD46 mutations is important in diagnosing and managing aHUS, and therapies targeting the complement system, such as eculizumab, are used to treat this condition.

Infectious Diseases:

• Given its role as a receptor for several viruses, CD46 is involved in the pathogenesis of measles, adenovirus infections, and HHV-6 infections. These pathogens exploit CD46 to enter host cells, and viral interaction with CD46 can lead to immune modulation, aiding in viral persistence and evasion of host defenses.
• Vaccination against measles and other CD46-utilizing viruses remains an important public health measure to prevent viral infections.

Cancer:

• CD46 expression is altered in some cancers, and it has been implicated in tumor immune evasion. By modulating complement activation, tumor cells expressing CD46 can escape complement-mediated lysis, promoting tumor survival.
• CD46 has been explored as a therapeutic target in cancer immunotherapy, with strategies aimed at blocking its complement-regulatory function to enhance tumor cell destruction by the immune system.

Autoimmune Diseases:

• CD46 is involved in maintaining immune balance, and its dysregulation has been linked to autoimmune diseases such as multiple sclerosis (MS) and systemic lupus erythematosus (SLE). In these conditions, altered CD46 signaling may contribute to inappropriate immune activation and tissue damage.

Summary

CD46 is a multifunctional glycoprotein that plays a crucial role in regulating the complement system, protecting host cells from complement-mediated damage. Structurally, CD46 consists of four complement control protein (CCP) domains, a transmembrane region, and a cytoplasmic tail, with multiple isoforms generated through alternative splicing. These isoforms have distinct roles in immune regulation and T-cell responses.

Beyond its complement-regulatory functions, CD46 is involved in viral pathogenesis as a receptor for viruses such as the measles virus and HHV-6. It also participates in immune modulation by promoting both Th1 responses and regulatory T cells (Tregs), which help balance immune activation and tolerance.

Clinically, CD46 is implicated in diseases such as atypical hemolytic uremic syndrome (aHUS), where mutations lead to excessive complement activation and tissue damage. It also plays a role in viral infections, cancer immune evasion, and autoimmune diseases, making it a target for therapeutic interventions aimed at modulating immune and complement responses. Understanding the diverse functions of CD46 is crucial for developing targeted therapies in complement-related disorders and immune diseases.