Nuclear Import of Cytoplasmic Poly(A) Binding Protein Restricts Gene Expression via Hyperadenylation and Nuclear Retention of mRNA

Abstract

Poly(A) tail length is emerging as an important marker of mRNA fate, where deviations from the canonical length can signal degradation or nuclear retention of transcripts. Pathways regulating polyadenylation thus have the potential to broadly influence gene expression. Here we demonstrate that accumulation of cytoplasmic poly(A) binding protein (PABPC) in the nucleus, which can occur during viral infection or other forms of cellular stress, causes mRNA hyperadenylation and nuclear accumulation of poly(A) RNA. This inhibits gene expression but does not affect mRNA stability. Unexpectedly, PABPC-induced hyperadenylation can occur independently of mRNA 3′-end processing yet requires the canonical mRNA poly(A) polymerase II. We find that nuclear PABPC-induced hyperadenylation is triggered by multiple divergent viral factors, suggesting that altering the subcellular localization of PABPC may be a commonly used mechanism to regulate cellular gene expression in a polyadenylation-linked manner.

We are grateful to Shinji Makino, Tullia Lindsten, Harold Smith, and Jens Lykke-Andersen for their generous sharing of reagents. We thank all members of the Glaunsinger lab for helpful discussions and critical reading of the manuscript.

This research was supported by grants from the NIH (grant R01CA136367), a W. M. Keck Foundation Distinguished Young Scholars Award, and a Burroughs Wellcome Foundation Investigators in the Pathogenesis of Infectious Disease Award to B.A.G.