CD74 is the MHC class II histocompatibility antigen gamma chain, also known as the HLA-DR antigen-associated invariant chain. It plays a key role in MHC class II antigen processing, stabilizing the peptide-free class II α/β heterodimer shortly after complex synthesis and directing the transport of the complex from the endoplasmic reticulum to the endosomal/lysosomal system, where antigen processing and peptide binding to MHC class II occur. It is also the cell surface receptor for the macrophage cytokine MIF. CD74 participates in biological processes such as B cell maturation, cell proliferation, and energy production. CD74 plays an important role in cardiovascular disease and cancer and is a potential therapeutic target.
Distribution of CD74
CD74 is mainly distributed in B cells, monocytes, Langerhans cells, dendritic cells and thymic epithelial cells, and is also expressed in epithelial cells.
(Data source: uniprot)
Structure of CD74
CD74 is a transmembrane protein encoded by chromosome 5. It consists of an N-terminal cytoplasmic region, a transmembrane domain, and a C-terminal extracellular domain. The extracellular region of CD74 contains multiple functional domains involved in binding to MHC class II molecules and other biological functions. CD74 forms a trimer structure on the cell surface, which facilitates its involvement in antigen presentation.
(Data source: Li QL, et al. Front Cardiovasc Med. 2023)
Biological functions of CD74
CD74 is a molecular chaperone of major histocompatibility complex class II (MHCII) molecules involved in exogenous antigen presentation. CD74 plays a crucial role in antigen presentation. Following synthesis in the endoplasmic reticulum, CD74 assembles into a homotrimer and then binds to three MHCII heterodimers (αβ) to form a nonamer (αβIi)3. CD74 occupies the MHCII binding groove, preventing endogenous peptides from binding to MHCII in the endoplasmic reticulum. CD74 formation is associated with its transmembrane region and trimerization domain (amino acid residues 134-208 in the C-terminal extracellular region). CD74 also participates in antigen presentation to MHC class I, activating CD8+ T cells and initiating MHC class I-mediated cytotoxic T cell responses. Furthermore, CD74 participates in MIF signaling, forming a complex with CXCR2, CXCR4, or CXCR7 to activate multiple signaling pathways, including ERK1/2, MAPK, and the PI3K-Akt cascade.
(Data source: Li QL, et al. Front Cardiovasc Med. 2023)
The relationship between CD74 and disease
CD74 plays a crucial role in cardiovascular diseases such as atherosclerosis, ischemic heart disease, and myocardial hypertrophy. In atherosclerosis, CD74 can form a complex with MIF, activating the CXCR2/CD74/CD44 signaling pathway, promoting monocyte chemotaxis and contributing to the development of atherosclerosis. Furthermore, CD74 is involved in MHCII folding, intracellular trafficking, and antigen peptide loading in atherosclerosis, thereby influencing the progression of atherosclerosis.
(Data source: Li QL, et al. Front Cardiovasc Med. 2023)
CD74 is highly expressed in a variety of tumor cells, such as breast cancer, lymphoma, multiple myeloma, non-small cell lung cancer, and chronic lymphocytic leukemia. In non-small cell lung cancer, CD74 and MIF influence immune cell polarization and tumor cell growth in the tumor microenvironment by regulating the activity of the HIF-1α/MIF/CD74 axis. Targeted inhibition of the MIF/CD74 signaling pathway can reduce AKT phosphorylation, thereby inhibiting tumor progression, and affect tumor growth and metastasis by regulating the phenotypic transformation of microglia. In addition, CD74 expression has been confirmed in non-small cell lung cancer, indicating that it may play an important role in tumor development.
(Data source: Liu L, et al. J Exp Clin Cancer Res. 2024)
Milatuzumab is an IgG1k anti-CD74 blocking monoclonal antibody designed to target B cells in lymphomas. It is used to treat multiple myeloma, non-Hodgkin's lymphoma, and chronic lymphocytic leukemia. Milatuzumab is also being investigated for the treatment of autoimmune diseases such as SLE. Current clinical data on milatuzumab's use in various tumors and autoimmune diseases will facilitate the transition of CD74-targeted therapies to the clinic for cardiovascular disease.
