PARN-Driven Alternative Polyadenylation Regulates Immunoglobulin Homeostasis in Antibody-Secreting Cells

Class switch recombination (CSR) is a programmed DNA recombination process that enables B cells to switch the isotype of antibodies they produce, thereby generating high-affinity immunoglobulins essential for adaptive immunity. Notably, systemic lupus erythematosus (SLE) frequently arises in the context of hypersensitivity; however, the precise mechanisms underlying its pathogenesis remain incompletely understood. Here, we demonstrate that poly(A)-specific ribonuclease (PARN), an RNA-binding protein, acts as a critical regulator of CSR. In antibody-secreting cells, loss of PARN impairs CSR, resulting in a reduced proportion of cells producing post-switched immunoglobulin isotypes. Mechanistically, PARN specifically binds to the enhancer motif UGUA and the polyadenylation signal AAUAAA. PARN subsequently promotes transcript 3’ UTR shortening through alternative polyadenylation to regulate RNA stability. Depletion of PARN contributes to widespread 3’ UTR lengthening across the transcriptome, notably affecting the Foxp1 transcript, and consequently impedes CSR efficiency. We further identified PTBP1 and PABP as cofactors that functionally cooperate with PARN to suppress CSR. Analysis of human datasets further reveals that Parn expression is elevated in patients with SLE. In an SLE mouse model, targeted Parn knockout in B lymphocytes undergoing CSR alleviates disease severity. This study unveils PARN as a key modulator of CSR in B cells, highlighting its therapeutic potential in SLE.