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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.

Author information

1
Immunology Research Center, National Health Research Institutes (NHRI), Zhunan, Miaoli County, Taiwan.
2
National Institute of Infectious Diseases and Vaccinology, NHRI, Zhunan, Miaoli County, Taiwan.
3
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
4
Department of Medical Research and Development, Chang Bing Show Chwan Memorial Hospital, Chang Hua, Taiwan.
5
Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA.
6
Immunology Research Center, National Health Research Institutes (NHRI), Zhunan, Miaoli County, Taiwan. yuwensu@nhri.org.tw.

Abstract

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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