Regulation of IgA secretion through PAD2-mediated citrullination of MZB1
Technical Research Assistant
Bo Sun, Benjamin Geary, Santanu Mondal, Ronak R. Tilvawala, Konstantin Tsoyi, Ivan O. Rosas, Paul R. Thompson, and I-Cheng Ho
Research Category: Allergy, Immunology, Inflammation, and Infectious Diseases
Approximately 60-70% of patients with rheumatoid arthritis (RA) have antibody against auto-antigens that have undergone citrullination, which is a unique form of post-translational modification converting peptidylarginine to peptidylcitrulline and is catalyzed by peptidylarginine deiminases (PADs), including PAD1-4 and PAD6 in mammals. Several major risk factors of RA are associated with hypercitrullination, which can alter the function of immune cells, such as T cells. Surprisingly, very little is known regarding the function of PADs in B cells, which produce anti-citrullinated protein antibodies and are very effective therapeutic targets of RA. In an unbiased citrullinomic analysis, we found that MZB1, an endoplasmic reticulum protein that is critical for the optimal secretion of IgA by plasma cells, was preferentially enriched in the pool of citrullinated lung proteins obtained from patients with RA-associated interstitial lung disease compared to those from other chronic lung diseases. Ablation of MZB1 or PAD2 in primary human B cells attenuated the secretion of IgA but not the differentiation of IgA-expressing plasmablasts. Mechanistically, PAD2 citrullinated MZB1 on at least three arginine residues, R2, R54, and R112; PAD2-mediated citrullination of MZB1 enhanced its interaction with IgA in vitro. Taken together, our data demonstrate that PAD2 promotes IgA secretion through citrullinating MZB1.
Rheumatoid arthritis (RA) is caused by patients’ immune cells attacking their own joint tissues, resulting in joint inflammation. Approximately 60-70% of patients with rheumatoid arthritis (RA) have antibodies against proteins that have undergone a unique form of modification called citrullination. Recent studies have further suggested that several major genetic and environmental risk factors of RA are associated with unregulated citrullination, resulting in altered function of several types of immune cells. By examining citrullinated proteins obtained from the lungs of patients with RA-associated lung diseases, we discovered a novel role of citrullination in regulating the function of B cells, which are the immune cells responsible for producing antibodies and a very effective therapeutic target of RA. Specifically, we found that citrullination promotes the secretion of antibodies by B cells. Our data may provide a molecular explanation for the link between unregulated citrullination and the production of RA-associated antibodies.