CD74 Gene Editing    

CD74, also known as the invariant chain of major histocompatibility complex (MHC) class II, functions as an MHC-II chaperone and participates in the trafficking of MHC-II molecules in antigen-presenting cells. It has been shown that CD74 may be expressed independently of MHC-II, and CD74 can bind to non-MHC-II proteins. In addition, CD74 is a cell membrane receptor for macrophage migration inhibitory factor (MIF), a pleiotropic cytokine that has pro-inflammatory and pro-tumorigenic properties. This ligand-receptor interaction may be a significant link between chronic inflammation and carcinogenesis. CD74 regulates intracellular trafficking and functions as a cell membrane receptor and a chaperone, modulating B, T, and dendritic cell responses and promoting tumor growth through increasing tumor cell survival or proliferation. Therefore, CD74 is considered a therapeutic target in malignancy. Besides, CD74 regulates proliferation, survival, and secretion of inflammatory and fibrosis mediators in non-immune and non-tumor cells. Therefore, CD74 may modulate tissue injury and homeostasis beyond its effect on immune regulation.

Figure 1. The role of CD74 in the MHCII antigen presentation pathway. (Schröder B., 2016)

The Bio-functions of CD74

In addition to the important role of CD74 molecules in the antigen presentation pathway, CD74 also regulates the trafficking of additional molecules, such as angiotensin II type I receptor (AT1). CD74 directly binds to AT1 early in the biosynthetic pathway, and prevents its intracellular trafficking. Therefore, coexpression of CD74 molecules causes AT1 accumulation in the ER and AT1 proteasomal degradation. CD74 significantly regulates DC motility, B-cell development, and thymic selection. CD74 controls the maturation of B cells by NF-λB p65/RelA homodimer and its coactivator TAFII105. MIF is a key cytokine closely related to autoimmune and inflammatory diseases. MIF attracts and subsequently retains activated immune cells from the periphery to the inflamed tissues. The biological effects of MIF are predominately mediated by its primary receptor, CD74. A comprehensive analysis recently shows that MIF controls the activation of CD74. Besides, CD74 is also involved in various inflammatory diseases by a series of mechanisms. HIV-1 Vpu can downregulate MHC class II through Vpu binding to the cytoplasmic domain of CD74. CD74 molecule binds to the amyloid-b (Ab) precursor protein and can inhibit Ab processing. CD74-induced alteration of Ab processing could improve Alzheimer’s disease-associated memory deficits in mice.

CD74 and Cancer

CD74 has also been detected in many haematological malignancies like multiple myeloma. Moreover, also in a wide spectrum of neoplasms, which are not of myeloid or lymphatic origin, CD74 expression has been observed. These include cancers of the breast, the gastrointestinal tract, the kidney, the bladder, the lung, the prostate, the pancreas and the central nervous system. This may reflect that in general many non-immune cells can induce CD74 under certain conditions. However, malignant neoplasms of the gastrointestinal tract were significantly higher CD74 expression levels than the corresponding normal tissues. Although intestinal adenomas were found to exhibit less CD74 than normal mucosa, CD74 protein levels were increased in dysplastic epithelial cells. In addition, a trend towards enhanced CD74 expression was observed in high grade pancreatic carcinomas. In gastric cancer, CD74 expression negatively correlated with the depth of invasion of the tumor and the patient's clinical stage. Similar tendencies were revealed upon analysis of CD74 in urothelial carcinomas of the bladder. Based on the expression of CD74 on malignant cells and limited expression on non-immune cells, at least under physiological conditions, a humanized monoclonal antibody targeting CD74, milatuzumab, has been developed. This agent is currently evaluated in clinical studies. Although particularly aimed at the treatment of B cell neoplasms, broader applicability may be imagined in the case of effectiveness with regard to the described expression of CD74 also in other tumors.

CD74 Gene Editing Services

CRISPR/Cas9 Platform^CB at Creative Biogene is dedicated to offering comprehensive CRISPR/Cas9 gene editing services and products for academic research, biotech research and pharmaceutical drug discovery. With deep gene editing knowledge and extensive experience in experimental operation and data processing, we help you effectively control CD74 genes knockout/knockin/point mutation in cells or animals via CRISPR/Cas9 technology.

Related Products at CRISPR/Cas9 Platform^CB