B-cell humoral response and differentiation is regulated by non-canonical poly(A) polymerase TENT5C

TENT5C is a non-canonical poly(A) polymerase (ncPAP) upregulated in activated B-cells and suppressing their proliferation. Herein we measured the global distribution of poly(A) tail lengths in responsive B-cells using a modified Nanopore direct RNA-sequencing approach and revealed that TENT5C polyadenylates immunoglobulin mRNAs regulating their steady-state levels. Consequently, TENT5C deficient B-cells secrete less antibodies and KO mice have diminished gamma globulin concentrations despite the increased number of CD138high plasma cells in the bone marrow and spleen as a consequence of accelerated differentiation. TENT5C is explicitly upregulated in differentiating plasma cells (PC) by innate signaling via selected toll-like receptors (TLR). Importantly, TENT5C deficiency in B lymphocytes impairs the capacity of the secretory pathway through the reduction of ER volume and downregulated unfolded protein response. Our findings define the role of the TENT5C enzyme in B-cell physiology and discover the first ncPAP engaged in the regulation of immunoglobulin mRNA poly(A) tails, thus serving as a regulator of humoral immunity.