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

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

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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 TH 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 TH 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 TH 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.

Original languageEnglish (US)
Pages (from-to)324-334
Number of pages11
JournalJournal of Allergy and Clinical Immunology
Volume145
Issue number1
DOIs
StatePublished - Jan 2020

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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