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ZAP isoforms regulate unfolded protein response and epithelial- mesenchymal transition

Phuong Thao Ly1, Shaohai Xu1, Melissa Wirawan2

  • 1School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.

Proceedings of the National Academy of Sciences of the United States of America
|July 26, 2022
PubMed

Insights

Human ZAP isoforms, ZAPL and ZAPS, regulate host mRNA stability and cellular processes like the unfolded protein response and cell migration. Modulating their balance offers new therapeutic avenues.

Area of Science:

  • Virology
  • Molecular Biology
  • Cell Biology

Background:

  • Human Zinc-finger Antiviral Protein (ZAP) inhibits viruses like HIV by targeting viral RNAs.
  • The roles of ZAP isoforms (ZAPL and ZAPS) in regulating host mRNAs and cellular functions remain largely uncharacterized.
  • Understanding ZAP isoform regulation is crucial for their antiviral functions and potential therapeutic applications.

Purpose of the Study:

  • To investigate the regulatory mechanisms controlling ZAP isoform production.
  • To identify host mRNA targets regulated by ZAP isoforms.
  • To elucidate the cellular functions influenced by ZAP isoforms, including the unfolded protein response (UPR) and epithelial-mesenchymal transition (EMT).

Main Methods:

  • Investigated ZAPS production inhibition by splicing factors hnRNPA1/A2, PTBP1/2, and U1-snRNP.
  • Utilized splice-switching antisense oligonucleotides to modulate ZAPL/S balance in human cells.
  • Performed transcriptomic analysis on ZAP-isoform-specific knockout cells.
  • Determined subcellular localization of ZAP isoforms using endogenous tagging.
  • Assessed ZAP isoform effects on UPR, ER stress, and EMT-related cell migration.

Main Results:

  • Splicing factors hnRNPA1/A2, PTBP1/2, and U1-snRNP inhibit ZAPS production.
  • Modulation of ZAPL/S balance is feasible using antisense oligonucleotides.
  • ZAPL and ZAPS target distinct sets of host mRNAs involved in UPR, EMT, and innate immunity.
  • ZAPL and ZAPS exhibit differential localization (membrane and cytosol, respectively), correlating with target specificity.
  • ZAP isoforms differentially regulate UPR branches, cell viability during ER stress, and EMT-related cell migration in a cell-type-dependent manner.

Conclusions:

  • The balance between ZAP splicing and other RNA processing pathways is a target for modulating ZAP isoform activity.
  • This study identifies novel host transcripts and cellular processes regulated by ZAP isoforms.
  • Findings provide insights into ZAP's multifaceted roles beyond direct antiviral activity, impacting fundamental cellular functions.
Keywords:
alternative splicingepithelial-mesenchymal transitionsplice-switching antisense oligonucleotidesunfolded protein responsezinc finger antiviral protein

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