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Cell Death Differ. 2019 Jul;26(7):1221-1234. doi: 10.1038/s41418-018-0199-z. Epub 2018 Sep 20.

PP4 deficiency leads to DNA replication stress that impairs immunoglobulin class switch efficiency.

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Immunology Research Center, National Health Research Institutes (NHRI), Zhunan, Miaoli County, Taiwan.
National Institute of Infectious Diseases and Vaccinology, NHRI, Zhunan, Miaoli County, Taiwan.
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Department of Medical Research and Development, Chang Bing Show Chwan Memorial Hospital, Chang Hua, Taiwan.
Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA.
Immunology Research Center, National Health Research Institutes (NHRI), Zhunan, Miaoli County, Taiwan.


The serine/threonine phosphatase PP4 has been implicated in DNA damage repair and cell cycle regulation through its dephosphorylation of specific substrates. We previously showed that PP4 is required for mouse B cell development, germinal center (GC) formation and immunoglobulin (Ig) class switch recombination (CSR). Here, we investigate the mechanisms underlying this requirement and demonstrate that murine PP4-deficient B lymphocytes have a defect in cell proliferation. Strikingly, the DNA damage response pathway that involves ATM/p53 and is linked to cell cycle arrest and impaired cell survival is strongly induced in these mutant B cells. In response to LPS + IL-4, stimuli that trigger IgG1 production, these PP4-deficient B cells show inefficient phosphorylation of ATR, leading to reduced retention of γH2AX-NBS1 complexes at sites of DNA damage, and compromised switching to IgG1. However, beyond the cell proliferation phase, conditional deletion of PP4 under the control of AID/cre completely restores normal IgG1 production in mutant B cell cultures. In vivo, co-deletion of PP4 and p53 by AID/cre partially rescues switching to IgG1 in B cells of mice immunized with TNP-KLH. Our findings establish that PP4 is indispensable for preventing DNA replication stress that could interfere with CSR, thereby promoting antibody switching during the humoral immune response.

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