The CD38 protein is a glycoprotein found on the surface of many cells throughout the body, acting as a cell surface marker. It is present on various cell types, including immune cells.
Understanding CD38’s Functions
CD38 performs a dual role within cells, functioning as both an enzyme and a receptor. As an enzyme, it primarily acts as an NAD glycohydrolase, breaking down nicotinamide adenine dinucleotide (NAD+) into nicotinamide (NAM) and adenosine diphosphate ribose (ADPR). This enzymatic activity influences cellular metabolism. Beyond its enzymatic action, CD38 also serves as a cell surface receptor. In this capacity, it participates in signal transduction, receiving external signals and transmitting them into the cell. For example, it interacts with CD31 to mediate cell adhesion and movement across barriers. These receptor functions enable CD38 to influence various biological events.
CD38’s Role in Immune Responses
CD38 is widely distributed across the immune system, appearing on various immune cells such as T cells, B cells, natural killer (NK) cells, monocytes, and macrophages. Its expression levels can vary depending on their stage of maturation or activation. CD38 can be found on the cell surface and also in intracellular compartments like the endoplasmic reticulum and nuclear membrane.
This protein contributes to a range of immune processes, including cell activation, proliferation, and adhesion. It also plays a part in cell migration, which is the movement of immune cells to sites of infection or inflammation. For instance, CD38 is involved in the infiltration of T cells and macrophages into the brain during certain conditions.
CD38 also influences the production of cytokines, which regulate immune responses. Its activity is particularly relevant during inflammatory responses and in autoimmune conditions, where it can regulate cell recruitment and cytokine release.
CD38’s Link to Metabolism and Aging
CD38 significantly impacts nicotinamide adenine dinucleotide (NAD+) metabolism. NAD+ is a coenzyme involved in numerous cellular processes, including energy production, cell signaling, and DNA repair. It is fundamental for cell health and longevity.
CD38 is a primary enzyme responsible for degrading NAD+ in mammalian tissues. This degradation leads to a decline in NAD+ levels, which is associated with the aging process and age-related metabolic conditions. Increased CD38 expression and activity occur with aging, contributing to NAD+ decline and issues like mitochondrial dysfunction.
The elevated CD38 activity in aging is hypothesized to be linked to chronic inflammation, where inflammatory cells expressing CD38 accumulate in tissues and consume NAD+. Inhibiting CD38 activity has been shown to preserve NAD+ levels and improve metabolic health in animal models, suggesting a strategy for addressing age-related cellular decline. CD38 also metabolizes nicotinamide mononucleotide (NMN), a precursor to NAD+, further indicating its influence on NAD+ availability.
CD38 in Disease and Treatment
CD38 is implicated in various diseases, notably certain cancers. It is a prominent therapeutic target in multiple myeloma, a type of plasma cell cancer. Multiple myeloma cells often express high levels of CD38 on their surface, making it an attractive target for intervention.
The understanding of CD38’s role has led to the development of specific therapies, primarily monoclonal antibodies. These antibodies, such as daratumumab and isatuximab, bind to CD38 on cancer cells. They work through several mechanisms, including directly inducing cell death (apoptosis) and engaging the body’s immune system to destroy cancer cells through processes like complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP).
These CD38-targeting antibodies also have immunomodulatory effects, such as eliminating certain immune suppressor cells, which can enhance the anti-tumor immune response. While primarily used in multiple myeloma, CD38’s involvement in other conditions like chronic inflammatory diseases and metabolic disorders suggests its broader medical relevance. Research continues into CD38-targeting therapies for diseases beyond hematological malignancies, including solid tumors and autoimmune disorders.