Wiskott-Aldrich syndrome protein senses irradiation-induced DNA damage to coordinate the cell-protective Golgi dispersal response in human T and B lymphocytes

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:145

Article

Wen, Kuo-Kuang ; Han, Seong-Su ; Vyas, Yatin M.

关键词: Primary immunodeficiency;    Wiskott-Aldrich syndrome;    Golgi morphology;    DNA damage;   

DOI  :  10.1016/j.jaci.2019.09.026

来源: Elsevier

【 摘 要 】

Background: Wiskott-Aldrich syndrome (WAS) is an X-linked primary immune deficiency disorder resulting from Wiskott-Aldrich syndrome protein (WASp) deficiency. Lymphocytes from patients with WAS manifest increased DNA damage and lymphopenia from cell death, yet how WASp influences DNA damage-linked cell survival is unknown. A recently described mechanism promoting cell survival after ionizing radiation (IR)-induced DNA damage involves fragmentation and dispersal of the Golgi apparatus, known as the Golgi-dispersal response (GDR), which uses the Golgi phosphoprotein 3 (GOLPH3)-DNA-dependent protein kinase (DNA-PK)-myosin XVIIIA-F-actin signaling pathway. Objective: We sought to define WASp's role in the DNA damage-induced GDR and its disruption as a contributor to the development of radiosensitivity-linked immunodeficiency in patients with WAS. Methods: In human T-H and B-cell culture systems, DNA damage-induced GDR elicited by IR or radiomimetic chemotherapy was monitored in the presence or absence of WASp or GOLPH3 alone or both together. Results: WASp deficiency completely prevents the development of IR-induced GDR in human T-H and B cells, despite the high DNA damage load. Loss of WASp impedes nuclear translocation of GOLPH3 and its colocalization with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Surprisingly, however, depletion of GOLPH3 alone or depolymerization of F-actin in WASp-sufficient T-H cells still allows development of robust GDR, suggesting that WASp, but not GOLPH3, is essential for GDR and cell survival after IR-induced DNA-damage in human lymphocytes. Conclusion: The study identifies WASp as a novel effector of the nucleus-to-Golgi cell-survival pathway triggered by IR-induced DNA damage in cells of the hematolymphoid lineage and proposes an impaired GDR as a new cause for development of a radiosensitive form of immune dysregulation in patients with WAS.

【 授权许可】

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