Immunoglobulin expression and the humoral immune response is regulated by the non-canonical poly(A) polymerase TENT5C

• Published in: Nature communications Vol. 11; no. 1; p. 2032
• Main Authors: Bilska, Aleksandra, Kusio-Kobiałka, Monika, Krawczyk, Paweł S., Gewartowska, Olga, Tarkowski, Bartosz, Kobyłecki, Kamil, Nowis, Dominika, Golab, Jakub, Gruchota, Jakub, Borsuk, Ewa, Dziembowski, Andrzej, Mroczek, Seweryn
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27-04-2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/31; 13/51; 38; 38/90; 38/91; 631/1647/514/1949; 631/250/2152/2153/1291; 631/337/1645/2570; 64/60; 82/1; 82/58; Animals; Antibodies; B-Lymphocytes - enzymology; Cell Differentiation; Cell proliferation; Enzymatic activity; Female; Gene Expression Regulation, Enzymologic; Gene sequencing; Humanities and Social Sciences; Immune response; Immune response (humoral); Immune system; Immunity, Humoral; Immunoglobulins; Immunoglobulins - metabolism; Lymphocytes B; Lymphocytes T; Male; Mice; Mice, Knockout; mRNA stability; multidisciplinary; Mutation; Nucleotidyltransferases - genetics; Nucleotidyltransferases - metabolism; Phenotype; Plasma cells; Polyadenine; Polyadenylation; Polynucleotide adenylyltransferase; Porosity; Protein folding; RNA-Seq; Science; Science (multidisciplinary); Signal Transduction; Unfolded Protein Response
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-15835-3

TENT5C is a non-canonical cytoplasmic poly(A) polymerase highly expressed by activated B cells to suppress their proliferation. Here we measure the global distribution of poly(A) tail lengths in responsive B cells using a Nanopore direct RNA-sequencing approach, showing that TENT5C polyadenylates immunoglobulin mRNAs regulating their half-life and consequently steady-state levels. TENT5C is upregulated in differentiating plasma cells by innate signaling. Compared with wild-type,
Tent5c
−/−
mice produce fewer antibodies and have diminished T-cell-independent immune response despite having more CD138
high
plasma cells as a consequence of accelerated differentiation. B cells from
Tent5c
−/−
mice also have impaired capacity of the secretory pathway, with reduced ER volume and unfolded protein response. Importantly, these functions of TENT5C are dependent on its enzymatic activity as catalytic mutation knock-in mice display the same defect as
Tent5c
−/−
. These findings define the role of the TENT5C enzyme in the humoral immune response.
Regulating polyadenylation is important for mRNA stability, which can in turn affect B cell maturation and humoral immune responses. Here the authors use Nanopore poly(A) sequencing to explore the importance of the cytoplasmic poly(A) polymerase TENT5C, particularly in the production of immunoglobulins.