FEZ1 phosphorylation regulates HSPA8 localization and interferon-stimulated gene expression

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

doi:10.1016/j.celrep.2022.110396

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 journal › Article › peer-review

5 Scopus citations

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 language	English (US)
Article number	110396
Journal	Cell reports
Volume	38
Issue number	7
DOIs	https://doi.org/10.1016/j.celrep.2022.110396
State	Published - Feb 15 2022

Funding

We thank Jeffrey Savas for performing mass spectrometry, and Yan Xiang, Paula Traktman, and David Evans for antibodies against VacV proteins. This work was supported by NIH grant R01 GM101975 (to M.H.N.), NIH grant R01 AI150559 (to M.H.N.), the Gilead Sciences Research Scholars Program in HIV (to J.F.H.), NIH grant K22 AI136691 (to J.F.H.), NIH grant R01 AI150998 (to J.F.H.), the NIH-supported Third Coast CFAR P30 AI117943 (to J.F.H.).

Keywords

DNA-PK
FEZ1
HSPA8
ISG responses

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2022.110396

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title = "FEZ1 phosphorylation regulates HSPA8 localization and interferon-stimulated gene expression",

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{\textquoteright}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.",

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author = "Viacheslav Malikov and Nathan Meade and Simons, {Lacy M.} and Hultquist, {Judd F.} and Naghavi, {Mojgan H.}",

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AU - Simons, Lacy M.

AU - Hultquist, Judd F.

AU - Naghavi, Mojgan H.

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N2 - 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.

AB - 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.

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FEZ1 phosphorylation regulates HSPA8 localization and interferon-stimulated gene expression

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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