CD74 - CD74 molecule |Elisa - Clia - Antibody - Protein

Background

CD74, also known as the invariant chain (Ii), is a type II transmembrane glycoprotein that plays a critical role in the immune system, particularly in antigen processing and presentation. CD74 is encoded by the CD74 gene and is primarily expressed on antigen-presenting cells (APCs) such as B cells, dendritic cells, and macrophages, although it is also found on some non-immune cells, including certain epithelial and cancer cells.

One of its central functions is to act as a chaperone for major histocompatibility complex class II (MHC-II) molecules, ensuring the proper folding, trafficking, and peptide loading of MHC-II, which is essential for the presentation of antigens to CD4+ T cells. In addition to its role in antigen presentation, CD74 also functions as a receptor for macrophage migration inhibitory factor (MIF), which modulates inflammatory responses and cell survival pathways.

Given its key roles in the immune system, CD74 is implicated in several pathological processes, including autoimmune diseases, inflammatory disorders, and cancer. Its involvement in these diseases makes CD74 a potential therapeutic target in a variety of clinical settings.

Protein Structure

CD74 is a type II transmembrane glycoprotein that exists in multiple isoforms due to alternative splicing. The most common isoforms are p31 and p41, with the numerical designation referring to their molecular weight in kilodaltons (kDa). These isoforms differ in their structure, particularly in their cytoplasmic and luminal domains, but they retain key functional domains required for interaction with MHC-II molecules.

The structural components of CD74 include:

N-terminal Cytoplasmic Domain:

• The N-terminus of CD74 is located in the cytoplasm and contains signals for intracellular trafficking. These signals direct the newly synthesized MHC-II-CD74 complex from the endoplasmic reticulum (ER) to the endosomal/lysosomal compartments, where antigen loading occurs. Specifically, the cytoplasmic tail has di-leucine motifs that interact with adaptor proteins for sorting within the endosomal pathway.
• This domain also contains phosphorylation sites that can regulate CD74’s interaction with other proteins and its role in signaling.

Transmembrane Domain:

• The transmembrane region anchors CD74 in the membrane and ensures its correct positioning within cellular compartments, such as the ER and Golgi apparatus, during the transport of MHC-II molecules.
• The transmembrane domain is essential for oligomerization, where multiple CD74 molecules cluster together, aiding in the stabilization of MHC-II complexes.

Extracellular/Luminal Domain:

• The extracellular (luminal) domain of CD74 is responsible for binding to the peptide-binding groove of MHC-II molecules. This binding ensures that the MHC-II molecule does not prematurely bind to peptides in the ER or Golgi and that it is properly folded and assembled before reaching the endosome for antigen loading.
• A notable feature of CD74 is the CLIP (class II-associated invariant chain peptide) region, which occupies the peptide-binding cleft of MHC-II, preventing inappropriate peptide binding. The CLIP sequence is eventually removed by HLA-DM in the endosomal compartments to allow antigen loading.
• In the case of the p41 isoform, an additional domain exists that interacts with cathepsin S, an enzyme involved in the degradation of CD74 to facilitate MHC-II antigen presentation.

Glycosylation:

• CD74 is highly glycosylated, with several N-linked glycosylation sites present in its luminal domain. These glycosylation sites are important for protein stability, trafficking, and interactions with other components in the antigen presentation machinery.

Classification and Subtypes

CD74 is classified as a type II transmembrane protein, characterized by its N-terminal intracellular domain and C-terminal luminal domain. It belongs to the MHC class II chaperone family and serves as the invariant chain that interacts with newly synthesized MHC-II molecules.

CD74 exists in multiple isoforms, the most prominent being p31 and p41:

• p31: This is the shorter and more common isoform, which primarily functions in MHC-II chaperoning and trafficking.
• p41: This isoform contains an additional segment that interacts with cathepsin S and may have a role in modulating the degradation of CD74 during MHC-II antigen loading.

CD74 can also exist in a soluble form (sCD74), which is released into the extracellular environment. Soluble CD74 has been detected in the serum of patients with autoimmune diseases and cancer, suggesting that it might play a role in modulating immune responses beyond its membrane-bound form.

Function and Biological Significance

The primary function of CD74 is in the antigen processing and presentation pathway, where it serves as a chaperone for MHC-II molecules. Beyond this role, CD74 has additional functions, including signaling and immune modulation, especially through its interaction with MIF.

MHC-II Chaperone Function:

• CD74 ensures the correct folding and assembly of MHC-II molecules in the ER. It binds to the peptide-binding groove of MHC-II molecules, preventing premature peptide loading and ensuring proper complex formation.
• Once MHC-II-CD74 complexes are transported to the endosomal compartments, CD74 undergoes proteolytic degradation, allowing the removal of the CLIP fragment by HLA-DM, which facilitates the binding of antigenic peptides to MHC-II.
• This process is essential for the presentation of exogenous antigens to CD4+ T cells, enabling the initiation of adaptive immune responses.

Signaling through MIF:

• CD74 acts as a receptor for macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine involved in innate and adaptive immune responses. The CD74-MIF interaction triggers intracellular signaling pathways that influence cell survival, inflammation, and immune regulation.
• Through its association with CD44, another surface molecule, CD74 can activate downstream signaling pathways such as MAPK and NF-κB, promoting cell proliferation, survival, and migration. This interaction is particularly important in the context of inflammation and cancer.

Role in Cancer:

• CD74 is overexpressed in a variety of tumors, including lymphomas, leukemias, and solid cancers such as breast and colorectal carcinoma. Its role in stabilizing MHC-II molecules and interacting with MIF supports tumor growth and survival by inhibiting apoptosis and promoting proliferation.
• CD74 also contributes to the immune evasion of tumor cells by regulating antigen presentation and modulating immune responses.

B Cell Function:

• In B cells, CD74 is involved in antigen processing and presentation, but it also serves as a co-receptor that regulates B cell proliferation and activation. CD74's interaction with MIF promotes B cell survival, especially during immune responses.

Clinical Issues

CD74 is implicated in several diseases due to its roles in antigen presentation and immune regulation:

Autoimmune Diseases:

• CD74 is highly expressed in autoimmune disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). Dysregulation of CD74 in these conditions may contribute to aberrant antigen presentation and abnormal immune activation, promoting chronic inflammation and autoimmunity.
• The soluble form of CD74 has been identified as a biomarker in several autoimmune diseases, and targeting the CD74-MIF axis is being explored as a potential therapeutic strategy in these conditions.

Cancer:

• CD74 is overexpressed in a variety of cancers, particularly B cell lymphomas and multiple myeloma. Its interaction with MIF provides survival signals that protect tumor cells from apoptosis, making CD74 a potential target for anticancer therapies.
• Antibodies targeting CD74 (e.g., milatuzumab) have been developed and tested in clinical trials for B cell malignancies, showing promise as a therapeutic strategy.

Chronic Inflammatory Diseases:

• CD74's role in modulating inflammatory responses via its interaction with MIF makes it a potential target in chronic inflammatory diseases, including atherosclerosis, inflammatory bowel disease (IBD), and asthma. Therapeutic interventions aimed at disrupting the CD74-MIF interaction could help mitigate inflammation in these conditions.

Alzheimer’s Disease:

• CD74 has also been implicated in the pathogenesis of Alzheimer’s disease (AD). It has been observed that CD74 interacts with amyloid precursor protein (APP), and its dysregulation may contribute to the progression of AD. Targeting CD74 could be a potential therapeutic strategy for modulating immune responses and neuroinflammation in AD.

Summary

CD74 is a multifunctional molecule with critical roles in antigen presentation, immune regulation, and inflammatory responses. As a chaperone for MHC-II molecules, it ensures proper antigen processing and presentation to CD4+ T cells, a key step in adaptive immunity. Additionally, CD74 serves as a receptor for macrophage migration inhibitory factor (MIF), influencing inflammation and cell survival. CD74 is implicated in various diseases, including autoimmune disorders, cancer, and chronic inflammatory conditions, making it an attractive target for therapeutic interventions. Understanding the molecular structure and function of CD74 is essential for developing new treatments for diseases involving immune dysregulation.