Translational regulation of viral secretory proteins by the 5' coding regions and a viral RNA-binding protein

Johan Nordholm; Jeanne Petitou; Henrik Östbye; Diogo V da Silva; Dan Dou; Hao Wang; Robert Daniels

doi:10.1083/jcb.201702102

Translational regulation of viral secretory proteins by the 5' coding regions and a viral RNA-binding protein

J Cell Biol. 2017 Aug 7;216(8):2283-2293. doi: 10.1083/jcb.201702102. Epub 2017 Jul 10.

Authors

Johan Nordholm¹, Jeanne Petitou¹, Henrik Östbye¹, Diogo V da Silva¹, Dan Dou¹, Hao Wang¹, Robert Daniels¹

Affiliation

¹ Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.

Abstract

A primary function of 5' regions in many secretory protein mRNAs is to encode an endoplasmic reticulum (ER) targeting sequence. In this study, we show how the regions coding for the ER-targeting sequences of the influenza glycoproteins NA and HA also function as translational regulatory elements that are controlled by the viral RNA-binding protein (RBP) NS1. The translational increase depends on the nucleotide composition and 5' positioning of the ER-targeting sequence coding regions and is facilitated by the RNA-binding domain of NS1, which can associate with ER membranes. Inserting the ER-targeting sequence coding region of NA into different 5' UTRs confirmed that NS1 can promote the translation of secretory protein mRNAs based on the nucleotides within this region rather than the resulting amino acids. By analyzing human protein mRNA sequences, we found evidence that this mechanism of using 5' coding regions and particular RBPs to achieve gene-specific regulation may extend to human-secreted proteins.

MeSH terms

3' Untranslated Regions
5' Untranslated Regions
A549 Cells
Animals
Binding Sites
COS Cells
Chlorocebus aethiops
Endoplasmic Reticulum / enzymology
HEK293 Cells
HeLa Cells
Hemagglutinin Glycoproteins, Influenza Virus / biosynthesis*
Hemagglutinin Glycoproteins, Influenza Virus / genetics
Humans
Influenza A Virus, H1N1 Subtype / enzymology*
Influenza A Virus, H1N1 Subtype / genetics
Neuraminidase / genetics
Neuraminidase / metabolism*
Protein Binding
Protein Biosynthesis
Protein Domains
RNA, Messenger / genetics
RNA, Messenger / metabolism*
RNA, Viral / genetics
RNA, Viral / metabolism*
Signal Recognition Particle / genetics
Signal Recognition Particle / metabolism
Transfection
Vero Cells
Viral Nonstructural Proteins / genetics
Viral Nonstructural Proteins / metabolism*
Viral Proteins / genetics
Viral Proteins / metabolism*

Substances

3' Untranslated Regions
5' Untranslated Regions
H1N1 virus hemagglutinin
Hemagglutinin Glycoproteins, Influenza Virus
INS1 protein, influenza virus
RNA, Messenger
RNA, Viral
Signal Recognition Particle
Viral Nonstructural Proteins
Viral Proteins
NA protein, influenza A virus
Neuraminidase