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PMID: 16847328 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

hnRNP A1 relocalization to the stress granules reflects a role in the stress response.

Molecular and cellular biology ·Vol. 26 ·No. 15 ·2006-08-00 ·Pages 5744-58

Guil S, Long JC, Cáceres JF

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.

MeSH Terms
Animals Cell Survival Cytoplasmic Granules/metabolism Enzyme Activation HeLa Cells Heterogeneous Nuclear Ribonucleoprotein A1 Heterogeneous-Nuclear Ribonucleoprotein Group A-B/genetics,metabolism Humans Intracellular Signaling Peptides and Proteins/genetics,metabolism Mice NIH 3T3 Cells Oxidative Stress Peptides/genetics,metabolism Phosphorylation Poly(A)-Binding Protein I/genetics,metabolism Poly(A)-Binding Proteins/genetics,metabolism Protein Serine-Threonine Kinases/genetics,metabolism RNA Interference RNA, Messenger/metabolism Recombinant Fusion Proteins/genetics,metabolism Signal Transduction/physiology T-Cell Intracellular Antigen-1
Chemicals
Heterogeneous Nuclear Ribonucleoprotein A1 Heterogeneous-Nuclear Ribonucleoprotein Group A-B Intracellular Signaling Peptides and Proteins Peptides Poly(A)-Binding Protein I Poly(A)-Binding Proteins RNA, Messenger Recombinant Fusion Proteins T-Cell Intracellular Antigen-1 TIA1 protein, human MKNK1 protein, human MKNK2 protein, human Protein Serine-Threonine Kinases
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Guil Sonia
Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, Scotland, United Kingdom.
Long Jennifer C
Cáceres Javier F
References (66)
66 references, click to expand
  1. Nuclear stress bodies: a heterochromatin affair?
    Nat Rev Mol Cell Biol. 2004 Jun;5(6):493-8 PMID: 15173828
  2. A key role for stress-induced satellite III transcripts in the relocalization of splicing factors into nuclear stress granules.
    J Cell Sci. 2004 Sep 1;117(Pt 19):4551-8 PMID: 15331664
  3. Isolation of an active gene encoding human hnRNP protein A1. Evidence for alternative splicing.
    J Mol Biol. 1989 Jun 5;207(3):491-503 PMID: 2760922
  4. Regulation of alternative pre-mRNA splicing by hnRNP A1 and splicing factor SF2.
    Cell. 1992 Jan 24;68(2):365-75 PMID: 1531115
  5. Shuttling of pre-mRNA binding proteins between nucleus and cytoplasm.
    Nature. 1992 Feb 20;355(6362):730-2 PMID: 1371331
  6. MAPKAP kinase-2; a novel protein kinase activated by mitogen-activated protein kinase.
    EMBO J. 1992 Nov;11(11):3985-94 PMID: 1327754
  7. The A1 and A1B proteins of heterogeneous nuclear ribonucleoparticles modulate 5' splice site selection in vivo.
    Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):6924-8 PMID: 8041722
  8. Regulation of alternative splicing in vivo by overexpression of antagonistic splicing factors.
    Science. 1994 Sep 16;265(5179):1706-9 PMID: 8085156
  9. Function of conserved domains of hnRNP A1 and other hnRNP A/B proteins.
    EMBO J. 1994 Nov 15;13(22):5483-95 PMID: 7957114
  10. MAPKs: new JNK expands the group.
    Trends Biochem Sci. 1994 Nov;19(11):470-3 PMID: 7855889
  11. A nuclear localization domain in the hnRNP A1 protein.
    J Cell Biol. 1995 May;129(3):551-60 PMID: 7730395
  12. Nucleo-cytoplasmic distribution of human hnRNP proteins: a search for the targeting domains in hnRNP A1.
    J Cell Sci. 1995 Feb;108 ( Pt 2):545-55 PMID: 7769000
  13. A nuclear export signal in hnRNP A1: a signal-mediated, temperature-dependent nuclear protein export pathway.
    Cell. 1995 Nov 3;83(3):415-22 PMID: 8521471
  14. General RNA binding proteins render translation cap dependent.
    EMBO J. 1996 Dec 16;15(24):7147-55 PMID: 9003790
  15. A role for the M9 transport signal of hnRNP A1 in mRNA nuclear export.
    J Cell Biol. 1997 Apr 7;137(1):27-35 PMID: 9105034
  16. Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2.
    EMBO J. 1997 Apr 15;16(8):1909-20 PMID: 9155017
  17. Role of the modular domains of SR proteins in subnuclear localization and alternative splicing specificity.
    J Cell Biol. 1997 Jul 28;138(2):225-38 PMID: 9230067
  18. Modulation of AUUUA response element binding by heterogeneous nuclear ribonucleoprotein A1 in human T lymphocytes. The roles of cytoplasmic location, transcription, and phosphorylation.
    J Biol Chem. 1997 Nov 7;272(45):28732-41 PMID: 9353343
  19. PRAK, a novel protein kinase regulated by the p38 MAP kinase.
    EMBO J. 1998 Jun 15;17(12):3372-84 PMID: 9628874
  20. Human eukaryotic translation initiation factor 4G (eIF4G) recruits mnk1 to phosphorylate eIF4E.
    EMBO J. 1999 Jan 4;18(1):270-9 PMID: 9878069
  21. Phosphorylation of the cap-binding protein eukaryotic translation initiation factor 4E by protein kinase Mnk1 in vivo.
    Mol Cell Biol. 1999 Mar;19(3):1871-80 PMID: 10022874
  22. Yeast shuttling SR proteins Npl3p, Gbp2p, and Hrb1p are part of the translating mRNPs, and Npl3p can function as a translational repressor.
    Mol Cell Biol. 2004 Dec;24(23):10479-91 PMID: 15542855
  23. Signal transduction pathways leading to increased eIF4E phosphorylation caused by oxidative stress.
    Free Radic Biol Med. 2005 Mar 1;38(5):631-43 PMID: 15683719
  24. Heterogeneous nuclear ribonucleoprotein A1 is a novel internal ribosome entry site trans-acting factor that modulates alternative initiation of translation of the fibroblast growth factor 2 mRNA.
    J Biol Chem. 2005 Feb 11;280(6):4144-53 PMID: 15525641
  25. Regulation of heterogenous nuclear ribonucleoprotein A1 transport by phosphorylation in cells stressed by osmotic shock.
    Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3605-10 PMID: 15738418
  26. Stress alters the subcellular distribution of hSlu7 and thus modulates alternative splicing.
    J Cell Sci. 2005 Mar 15;118(Pt 6):1151-9 PMID: 15728250
  27. A novel SR-related protein is required for the second step of Pre-mRNA splicing.
    Mol Cell Biol. 2005 Apr;25(8):2969-80 PMID: 15798186
  28. RNA decapping inside and outside of processing bodies.
    Curr Opin Cell Biol. 2005 Jun;17(3):326-31 PMID: 15901504
  29. Stress granules and processing bodies are dynamically linked sites of mRNP remodeling.
    J Cell Biol. 2005 Jun 20;169(6):871-84 PMID: 15967811
  30. Roles of heterogeneous nuclear ribonucleoproteins A and B in cell proliferation.
    J Cell Sci. 2005 Jul 15;118(Pt 14):3173-83 PMID: 16014382
  31. Regulation of Fas alternative splicing by antagonistic effects of TIA-1 and PTB on exon definition.
    Mol Cell. 2005 Aug 19;19(4):475-84 PMID: 16109372
  32. The Mnks are novel components in the control of TNF alpha biosynthesis and phosphorylate and regulate hnRNP A1.
    Immunity. 2005 Aug;23(2):177-89 PMID: 16111636
  33. Identification and functional outcome of mRNAs associated with RNA-binding protein TIA-1.
    Mol Cell Biol. 2005 Nov;25(21):9520-31 PMID: 16227602
  34. Reversible phosphorylation differentially affects nuclear and cytoplasmic functions of splicing factor 2/alternative splicing factor.
    Proc Natl Acad Sci U S A. 2005 Oct 18;102(42):15042-7 PMID: 16210245
  35. The MKK(3/6)-p38-signaling cascade alters the subcellular distribution of hnRNP A1 and modulates alternative splicing regulation.
    J Cell Biol. 2000 Apr 17;149(2):307-16 PMID: 10769024
  36. The RNA-binding protein TIA-1 is a novel mammalian splicing regulator acting through intron sequences adjacent to a 5' splice site.
    Mol Cell Biol. 2000 Sep;20(17):6287-99 PMID: 10938105
  37. Dynamic shuttling of TIA-1 accompanies the recruitment of mRNA to mammalian stress granules.
    J Cell Biol. 2000 Dec 11;151(6):1257-68 PMID: 11121440
  38. The mitogen-activated protein kinase signal-integrating kinase Mnk2 is a eukaryotic initiation factor 4E kinase with high levels of basal activity in mammalian cells.
    Mol Cell Biol. 2001 Feb;21(3):743-54 PMID: 11154262
  39. Phosphorylation by Sky1p promotes Npl3p shuttling and mRNA dissociation.
    RNA. 2001 Feb;7(2):302-13 PMID: 11233987
  40. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation.
    Physiol Rev. 2001 Apr;81(2):807-69 PMID: 11274345
  41. Translation initiation control by heme-regulated eukaryotic initiation factor 2alpha kinase in erythroid cells under cytoplasmic stresses.
    Mol Cell Biol. 2001 Dec;21(23):7971-80 PMID: 11689689
  42. Stress-induced nuclear bodies are sites of accumulation of pre-mRNA processing factors.
    Mol Biol Cell. 2001 Nov;12(11):3502-14 PMID: 11694584
  43. Nucleocytoplasmic shuttling of polypyrimidine tract-binding protein is uncoupled from RNA export.
    Mol Biol Cell. 2001 Dec;12(12):3808-20 PMID: 11739782
  44. The apoptosis-promoting factor TIA-1 is a regulator of alternative pre-mRNA splicing.
    Mol Cell. 2000 Nov;6(5):1089-98 PMID: 11106748
  45. Evidence that ternary complex (eIF2-GTP-tRNA(i)(Met))-deficient preinitiation complexes are core constituents of mammalian stress granules.
    Mol Biol Cell. 2002 Jan;13(1):195-210 PMID: 11809833
  46. hnRNP A1 nucleocytoplasmic shuttling activity is required for normal myelopoiesis and BCR/ABL leukemogenesis.
    Mol Cell Biol. 2002 Apr;22(7):2255-66 PMID: 11884611
  47. Messenger-RNA-binding proteins and the messages they carry.
    Nat Rev Mol Cell Biol. 2002 Mar;3(3):195-205 PMID: 11994740
  48. Human chromosomes 9, 12, and 15 contain the nucleation sites of stress-induced nuclear bodies.
    Mol Biol Cell. 2002 Jun;13(6):2069-79 PMID: 12058070
  49. Ischemia induces a translocation of the splicing factor tra2-beta 1 and changes alternative splicing patterns in the brain.
    J Neurosci. 2002 Jul 15;22(14):5889-99 PMID: 12122051
  50. Cell signalling and the control of pre-mRNA splicing.
    Nat Rev Mol Cell Biol. 2004 Sep;5(9):727-38 PMID: 15340380
  51. Intronic binding sites for hnRNP A/B and hnRNP F/H proteins stimulate pre-mRNA splicing.
    PLoS Biol. 2006 Feb;4(2):e21 PMID: 16396608
  52. HuR binding to cytoplasmic mRNA is perturbed by heat shock.
    Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3073-8 PMID: 10737787
  53. Bringing the role of mRNA decay in the control of gene expression into focus.
    Trends Genet. 2004 Oct;20(10):491-7 PMID: 15363903
  54. Immunopurification of heterogeneous nuclear ribonucleoprotein particles reveals an assortment of RNA-binding proteins.
    Genes Dev. 1988 Feb;2(2):215-27 PMID: 3129338
  55. Heat shock but not other stress inducers leads to the disruption of a sub-set of snRNPs and inhibition of in vitro splicing in HeLa cells.
    EMBO J. 1988 Nov;7(11):3509-18 PMID: 2974799
  56. Signals and their transduction pathways regulating alternative splicing: a new dimension of the human genome.
    Hum Mol Genet. 2002 Oct 1;11(20):2409-16 PMID: 12351576
  57. Stress granules: sites of mRNA triage that regulate mRNA stability and translatability.
    Biochem Soc Trans. 2002 Nov;30(Pt 6):963-9 PMID: 12440955
  58. The human LSm1-7 proteins colocalize with the mRNA-degrading enzymes Dcp1/2 and Xrnl in distinct cytoplasmic foci.
    RNA. 2002 Dec;8(12):1489-501 PMID: 12515382
  59. A novel splicing regulator shares a nuclear import pathway with SR proteins.
    EMBO J. 2003 Mar 17;22(6):1359-69 PMID: 12628928
  60. The RasGAP-associated endoribonuclease G3BP assembles stress granules.
    J Cell Biol. 2003 Mar 17;160(6):823-31 PMID: 12642610
  61. Protein kinase A phosphorylation modulates transport of the polypyrimidine tract-binding protein.
    Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8776-81 PMID: 12851456
  62. The GW182 protein colocalizes with mRNA degradation associated proteins hDcp1 and hLSm4 in cytoplasmic GW bodies.
    RNA. 2003 Oct;9(10):1171-3 PMID: 13130130
  63. Small interfering RNA-mediated reduction in heterogeneous nuclear ribonucleoparticule A1/A2 proteins induces apoptosis in human cancer cells but not in normal mortal cell lines.
    Cancer Res. 2003 Nov 15;63(22):7679-88 PMID: 14633690
  64. Stress-induced transcription of satellite III repeats.
    J Cell Biol. 2004 Jan 5;164(1):25-33 PMID: 14699086
  65. Dephosphorylated SRp38 acts as a splicing repressor in response to heat shock.
    Nature. 2004 Feb 5;427(6974):553-8 PMID: 14765198
  66. Cytoplasmic foci are sites of mRNA decay in human cells.
    J Cell Biol. 2004 Apr12;165(1):31-40 PMID: 15067023
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.00224-06
Published
2006-08-00
Pages
5744-58
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1592774
Subset
IM
Grants
Medical Research Council · MC_U127584479 · United Kingdom
External Links
PubMed source DOI: 10.1128/MCB.00224-06 PMC Full Text View journal details
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