Work

Protein kinase GIα oxidation negatively regulates antibody production by B cells

Year: 2025

Type: article

Abstract: Endogenous oxidants induce a C42-dependent interprotein disulfide between the subunits of protein kinase G (PKG) Iα in cardiovascular tissues to control blood pressure and ventricular diastolic relaxation. PKGIα is expressed in other cell types, including those of the immune system where the redox state of this kinase is likely to regulate other important physiological processes. The role of PKGIα oxidation in antibody production by B cells, which produce oxidants such as hydrogen peroxide during differentiation, was examined by comparing the immune response of oxidation-resistant C42S PKGIα knock-in (KI) mice to their wild type (WT) littermates. Immunization with the 4-hydroxy-3-nitrophenyl acetyl (NP)-chicken gamma globulin increased NP+ B cells (NP+B220+), IgG1+ B cells (NP+IgG1+B220+) and plasma B cells (NP+CD138+B220+) in spleen, with these responses being significantly potentiated in KI mice. The C42S PKGIα KI mice also secreted significantly more NP+ IgG1 antibody in their plasma compared to WTs. PKGIα physically interacted with activation-induced cytidine deaminase (AID), an essential enzyme for antibody diversity by deamination of cytosine to uracil in DNA, phosphorylating it at S38 to increase activity. Oxidation of PKGIα to the interprotein disulfide state decreased its binding and phosphorylation of AID S38 as determined using in vitro or ex vivo co-immunoprecipitation studies, together with kinase and immunoglobulin class-switching assays. In conclusion, PKGIα C42 oxidation in B cells decreases its interaction with and phosphorylation of AID, thereby reducing their antibody production.

Source: Redox Biology

DOI: 10.1016/j.redox.2025.103894