FEZ1 phosphorylation regulates HSPA8 localization and interferon-stimulated gene expression

Viacheslav Malikov, Nathan Meade, Lacy M. Simons, Judd F. Hultquist, Mojgan H. Naghavi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Fasciculation and elongation protein zeta-1 (FEZ1) is a multifunctional kinesin adaptor involved in processes ranging from neurodegeneration to retrovirus and polyomavirus infection. Here, we show that, although modulating FEZ1 expression also impacts infection by large DNA viruses in human microglia, macrophages, and fibroblasts, this broad antiviral phenotype is associated with the pre-induction of interferon-stimulated genes (ISGs) in a STING-independent manner. We further reveal that S58, a key phosphorylation site in FEZ1’s kinesin regulatory domain, controls both binding to, and the nuclear-cytoplasmic localization of, heat shock protein 8 (HSPA8), as well as ISG expression. FEZ1- and HSPA8-induced changes in ISG expression further involved changes in DNA-dependent protein kinase (DNA-PK) accumulation in the nucleus. Moreover, phosphorylation of endogenous FEZ1 at S58 was reduced and HSPA8 and DNA-PK translocated to the nucleus in cells stimulated with DNA, suggesting that FEZ1 is a regulatory component of the recently identified HSPA8/DNA-PK innate immune pathway.

Original languageEnglish (US)
Article number110396
JournalCell reports
Volume38
Issue number7
DOIs
StatePublished - Feb 15 2022

Keywords

  • DNA-PK
  • FEZ1
  • HSPA8
  • ISG responses

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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