The Influenza A Virus Endoribonuclease PA-X Usurps Host mRNA Processing Machinery to Limit Host Gene Expression

Lea Gaucherand, Brittany K. Porter, Rachel E. Levene, Emma L. Price, Summer K. Schmaling, Chris H. Rycroft, Yuzo Kevorkian, Craig McCormick, Denys A. Khaperskyy, Marta M. Gaglia

Research output: Contribution to journalArticlepeer-review

71 Citations (Scopus)

Abstract

Many viruses shut off host gene expression to inhibit antiviral responses. Viral proteins and host proteins required for viral replication are typically spared in this process, but the mechanisms of target selectivity during host shutoff remain poorly understood. Using transcriptome-wide and targeted reporter experiments, we demonstrate that the influenza A virus endoribonuclease PA-X usurps RNA splicing to selectively target host RNAs for destruction. Proximity-labeling proteomics reveals that PA-X interacts with cellular RNA processing proteins, some of which are partially required for host shutoff. Thus, PA-X taps into host nuclear pre-mRNA processing mechanisms to destroy nascent mRNAs shortly after their synthesis. This mechanism sets PA-X apart from other viral host shutoff proteins that target actively translating mRNAs in the cytoplasm. Our study reveals a unique mechanism of host shutoff that helps us understand how influenza viruses suppress host gene expression.

Original languageEnglish
Pages (from-to)776-792.e7
JournalCell Reports
Volume27
Issue number3
DOIs
Publication statusPublished - Apr 16 2019

Bibliographical note

Funding Information:
We thank Albert Tai and the personnel of the Tufts University Core Facility - Genomics Core for help with the RNA-seq. We thank Alejandro Cohen of the Dalhousie Proteomics and Mass Spectrometry Core Facility for support of the BioID proteomics analysis. We thank Andrew Mehle and Richard Webby for constructs, Claire Moore and Andrew Bohm for suggestions and feedback, and members of the Gaglia and McCormick labs for critical reading of the manuscript. This work was supported by a Natalie V. Zucker award from Tufts University (to M.M.G.), NIH grant R01 AI137358 (to M.M.G.), and Canadian Institutes for Health Research grant MOP-136817 (to C.M.). L.G. was supported by NIH training grant T32 GM007310. R.E.L. and Y.K. were supported by NIH training grant T32 AI007422. C.H.R. was partially supported by the Applied Mathematics Program of the US Department of Energy (DOE) Office of Advanced Scientific Computing Research under contract number DE-AC02-05CH11231. Conceptualization, C.M. D.A.K. M.M.G.; Investigation, L.G. B.K.P. R.E.L. E.L.P. S.K.S, Y.K. D.A.K. and M.M.G.; Formal Analysis, C.H.R. and M.M.G.; Writing, L.G. R.E.L. C.M. D.A.K. and M.M.G.; Funding Acquisition, C.M. and M.M.G. The authors declare no competing interests.

Funding Information:
We thank Albert Tai and the personnel of the Tufts University Core Facility - Genomics Core for help with the RNA-seq. We thank Alejandro Cohen of the Dalhousie Proteomics and Mass Spectrometry Core Facility for support of the BioID proteomics analysis. We thank Andrew Mehle and Richard Webby for constructs, Claire Moore and Andrew Bohm for suggestions and feedback, and members of the Gaglia and McCormick labs for critical reading of the manuscript. This work was supported by a Natalie V. Zucker award from Tufts University (to M.M.G.), NIH grant R01 AI137358 (to M.M.G.), and Canadian Institutes for Health Research grant MOP-136817 (to C.M.). L.G. was supported by NIH training grant T32 GM007310 . R.E.L. and Y.K. were supported by NIH training grant T32 AI007422 . C.H.R. was partially supported by the Applied Mathematics Program of the US Department of Energy (DOE) Office of Advanced Scientific Computing Research under contract number DE-AC02-05CH11231 .

Publisher Copyright:
© 2019 The Authors

ASJC Scopus Subject Areas

  • General Biochemistry,Genetics and Molecular Biology

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

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