PICH Supports Embryonic Hematopoiesis by Suppressing a cGAS-STING-Mediated Interferon Response

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  • Xinwei Geng
  • Chao Zhang
  • Miao Li
  • Jiaqi Wang
  • Fang Ji
  • Hanrong Feng
  • Meichun Xing
  • Fei Li
  • Lingling Zhang
  • Wen Li
  • Zhihua Chen
  • Hickson, Ian David
  • Huahao Shen
  • Songmin Ying

The Plk1-interacting checkpoint helicase (PICH) protein localizes to ultrafine anaphase DNA bridges in mitosis along with a complex of DNA repair proteins. Previous studies show PICH deficiency-induced embryonic lethality in mice. However, the function of PICH that is required to suppress embryonic lethality in PICH-deficient mammals remains to be determined. Previous clinical studies suggest a link between PICH deficiency and the onset of acquired aplastic anemia. Here, using Pich knock-out (KO) mouse models, the authors provide evidence for a mechanistic link between PICH deficiency and defective hematopoiesis. Fetal livers from Pich-KO embryos exhibit a significantly elevated number of hematopoietic stem cells (HSCs); however, these HSCs display a higher level of apoptosis and a much-reduced ability to reconstitute a functional hematopoietic system when transplanted into lethally irradiated recipients. Moreover, these HSCs show an elevated cytoplasmic dsDNA expression and an activation of the cGAS-STING pathway, resulting in excessive production of type I interferons (IFN). Importantly, deletion of Ifnar1 or cGAS reverses the defective hematopoiesis. The authors conclude that loss of PICH results in defective hematopoiesis via cGAS-STING-mediated type I IFN production.

Original languageEnglish
Article number2103837
JournalAdvanced Science
Volume9
Issue number7
DOIs
Publication statusPublished - 2022

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© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH

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