Effect of ZNT7 on the CD40 signaling pathway in B lymphocytes: a possible mechanism for a regulatory role of zinc in immune function

Abstract

Zinc deficiency impairs the immune system leading to frequent infections. Although it is known that zinc plays critical roles in maintaining healthy immune function, the underlying molecular targets are largely unknown. In this study, we demonstrate that zinc is important for the CD154‐CD40‐mediated activation of downstream signaling pathways in human B lymphocytes. CD40 is a receptor localized on the cell surface of many immune cells, including B lymphocytes. When the T helper lymphocyte (Th) is activated by antigens, it expresses a membrane protein, CD154 that allows Th to bind to B cells via CD154‐CD40 interaction leading to B cell activation. We show that cellular zinc deficiency impaired the CD154‐CD40‐mediated p38 MAPK phosphorylation. Most importantly, we demonstrate that ZNT7 interacted with CD40. ZNT7 knockdown in B lymphocytes had a negative effect on the cell surface expression of CD40. Consequently, the CD40‐mediated p38 MAPK signaling transduction was down‐regulated in ZNT7KD B lymphocytes. Conversely, this p38 MAPK signaling activity was up‐regulated by over‐expression of ZNT7 in B lymphocytes. We conclude that prevention of zinc deficiency is a key to maintain an optimal function of immune system and CD40 is the molecule target for ZNT7 in regulation of immune function of B lymphocytes.Support or Funding InformationThis work was supported by the United States Department of Agriculture, ARS CRIS project 2032‐51000‐004‐00D.