hnRNP A1 Relocalization to the Stress Granules Reflects a Role in the Stress Response

Abstract

hnRNP A1 is a nucleocytoplasmic shuttling protein that is involved in many aspects of mRNA metabolism. We have previously shown that activation of the p38 stress-signaling pathway in mammalian cells results in both hyperphosphorylation and cytoplasmic accumulation of hnRNP A1, affecting alternative splicing regulation in vivo. Here we show that the stress-induced cytoplasmic accumulation of hnRNP A1 occurs in discrete phase-dense particles, the cytoplasmic stress granules (SGs). Interestingly, mRNA-binding activity is required for both phosphorylation of hnRNP A1 and localization to SGs. We also show that these effects are mediated by the Mnk1/2 protein kinases that act downstream of p38. Finally, depletion of hnRNP A1 affects the recovery of cells from stress, suggesting a physiologically significant role for hnRNP A1 in the stress response. Our data are consistent with a model whereby hnRNP A1 recruitment to SGs involves Mnk1/2-dependent phosphorylation of mRNA-bound hnRNP A1.

We thank Rikiro Fukunaga (Osaka, Japan), Akila Mayeda (Miami, Fla.), Bertrand Seraphin (Paris, France) and Jamal Tazi (Montpellier, France) for their generous gifts of reagents. We also thank Inga Thomson (MRC HGU) for help with the FRAP experiments. We are grateful to Juan Valcarcel (Barcelona, Spain), Wendy Bickmore, and Jeremy Sanford (MRC HGU) for helpful comments on the manuscript.

This work was supported by the Medical Research Council (J.C.L. and J.F.C.) and a long-term postdoctoral fellowship from EMBO (S.G.).