hnRNP complexes: Composition, structure, and function

Current Opinion in Cell Biology

Volumn 11, Issue 3, 1999, Pages 363-371

  Krecic, Annette M ^a   Swanson, Maurice S ^b  

^a NORTHWESTERN UNIVERSITY   (United States)

^b UNIVERSITY OF FLORIDA COLLEGE OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN; MESSENGER RNA PRECURSOR; RNA BINDING PROTEIN; RNA POLYMERASE II;

ALTERNATIVE RNA SPLICING; CELL NUCLEUS; CYTOPLASM; GENETIC RECOMBINATION; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE; REVIEW; RNA PROCESSING; RNA TRANSCRIPTION; RNA TRANSLATION; TELOMERE;

EID: 0033153348     PISSN: 09550674     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0955-0674(99)80051-9     Document Type: Review

References (62)

1. Dreyfuss G, Matunis MJ, Piñol-Roma S, Burd CG: hnRNP proteins and the biogenesis of mRNA. Annu Rev Biochem 1993, 62:289-321.
2. Swanson MS: Functions of nuclear pre-mRNA/mRNA binding proteins. In Pre-mRNA Processing. Edited by Lamond AI. Berlin: Springer Verlag; 1995:17-33.
3. McAfee JG, Huang M, Soltaninassab S, Rech JE, Iyengar S, LeStourgeon WM: The packaging of pre-mRNA. In Eukaryotic mRNA Processing. Edited by Krainer AR. IRL Press at Oxford University Press; 1997:68-102.
4. Cartegni L, Maconi M, Morandi E, Cobianchi F, Riva S, Biamonti G: hnRNP A1 selectively interacts through its Gly-rich domain with different RNA-binding proteins. J Mol Biol 1996, 259:337-348.
5. Kiseleva E, Visa N, Wurtz T, Daneholt B: Immunocytochemical evidence for a stepwise assembly of Balbiani ring premessenger ribonucleoprotein particles. Eur J Cell Biol 1997, 74:407-416. The question of whether hnRNP complex structures are dynamic or static is addressed. The association of hrp36 - which is structurally related to hnRNP A1 - with the BR pre-mRNP particle is studied using immunoelectron microscopy. This hnRNP binds along the entire length of the BR pre-mRNA during transcription. Following particle maturation, hrp36 becomes buried in the complex suggesting that hnRNP complexes undergo a series of conformational rearrangements during mRNA biogenesis.
6. Sun X, Alzhanova-Ericsson AT, Visa N, Aissouni Y, Zhao J, Daneholt B: The hrp23 protein in the Balbiani ring pre-mRNP particles is released just before or at the binding of the particles to the nuclear pore complex. J Cell Biol 1998, 142:1181-1193.
7. Shahied-Milam L, Soltaninassab SR, Iyer GV, Lestourgeon WM: The heterogeneous nuclear ribonucleoprotein C protein tetramer binds U1, U2, and U6 snRNAs through its high affinity RNA binding domain (the bZIP-like motif). J Biol Chem 1998, 273:21359-21367.
8. Soltaninassab SR, McAfee JG, Shahied-Milam L, Lestourgeon WM: Oligonucleotide binding specificities of the hnRNP C protein tetramer. Nucleic Acids Res 1998, 26:3410-3417.
9. Sperling R, Koster AJ, Melamed-Bessudo C, Rubinstein A, Angenitzki M, Berkovitch-Yellin Z, Sperling J: Three-dimensional image reconstruction of large nuclear RNP (lnRnp) particles by automated electron tomography. J Mol Biol 1997, 267:570-583.
10. Müller S, Wolpensinger B, Angenitzki M, Engel A, Sperling J, Sperling R: A supraspliceosome model for large nuclear ribonucleoprotein particles based on mass determinations by scanning transmission electron microscopy. J Mol Biol 1998, 283:383-394.
11. Nakielny S, Dreyfuss G: Nuclear export of proteins and RNAs. Curr Opin Cell Biol 1997, 9:420-429.
12. Carson JH, Kwon S, Barbarese E: RNA trafficking in myelinating cells. Curr Opin Neurobiol 1998, 8:607-612.
13. Michelotti EF, Michelotti GA, Aronsohn AI, Levens D: Heterogeneous nuclear ribonucleoprotein K is a transcription factor. Mol Cell Biol 1996, 16:2350-2360.
14. Tomonaga T, Michelotti GA, Libutti D, Uy A, Sauer B, Levens D: Unrestraining genetic processes with a protein-DNA hinge. Mol Cell 1998, 1:759-764. The effect of a single stranded DNA (ssDNA) region positioned between two loxP sites on Cre-mediated site-specific recombination is tested. The ssDNA c-myc CT-element increases recombination frequency in vivo and recombinant hnRNP K augments CT-dependent recombination in vitro. The results support a model in which a protein-ssDNA 'hinge' alters chromatin structure to allow interactions between factors bound at distal cis-acting sites.
15. Du Q, Melnikova IN, Gardner PD: Differential effects of heterogeneous nuclear ribonucleoprotein K on Sp1- and Sp3- mediated transcriptional activation of a neuronal nicotinic acetylcholine receptor promoter. J Biol Chem 1998, 273:19877-19883. hnRNP K is identified as a factor that binds the pyrimidine-rich E1 promoter element of the neuronal acetylcholine receptor (nACh) β4 subunit gene. Cotransfection experiments are described using Drosophila SL2 cells that do not endogenously express hnRNP K or the Sp1 transcription factor. The authors show that hnRNP K antagonizes Sp1-mediated transactivation of the nACh β4 promoter probably by interfering with the dsDNA-binding activity of Sp1 to the adjacent E2 element.
16. Miau L-H, Chang C-J, Shen B-J, Tsai W-H, Lee S-C: Identification of heterogeneous nuclear ribonucleoprotein K (hnRNP K) as a repressor of C/EBP β-mediated gene activation. J Biol Chem 1998, 273:10784-10791.
17. Dempsey LA, Hanakahi LA, Maizels N: A specific isoform of hnRNP D interacts with DNA in the LR1 heterodimer: Canonical RNA binding motifs in a sequence-specific duplex DNA binding protein. J Biol Chem 1998, 273:29224-29229. The LR1 factor binds to double stranded DNA sites in immunoglobulin heavy chain switch regions and activates transcription from the c-myc P1 and the Epstein-Barr virus F promoters. This paper demonstrates that LR1 binds with high affinity and sequence specificity, and that it is a heterodimer composed of a specific hnRNP D isoform (M20) and nucleolin. Remarkably, other hnRNP D isoforms (M07, M27) are inhibitory to LR1 dsDNA binding activity in vitro.
18. Dempsey LA, Sun H, Hanakahi LA, Maizels N: G4 DNA binding by LR1 and its subunits, nucleolin and hnRNP D, a role for G-G pairing in immunoglobulin switch recombination. J Biol Chem 1999, 274:1066-1071. The LR1 heterodimer binds with high affinity to synthetic oligonucleotides which contain G - G base pairs as well as G-rich ssDNA. Each of the LR1 subunits, hnRNP D/M20 and nucleolin also independently bind to G4 DNA. Immunoglobulin heavy chain switch regions are also known to form G4 DNA in vitro. A model is proposed in which LR1 promotes switch recombination between donor and acceptor regions by binding to G - G paired structures in two different switch regions.
19. n. Mol Cell Biol 1993, 13:4301-4310.
20. Labranche H, Dupuis S, Bed-David Y, Bani M-R, Wellinger RJ, Chabot B: Telomere elongation by hnRNP A1 and a derivative that interacts with telomeric repeats and telomerase. Nat Genet 1998, 19:199-202. Telomere length is shown to be dependent on hnRNP A1 expression in transformed mouse erythroleukemic cell lines. Loss of hnRNP A1, due to retroviral insertions at the Hnrpa1 locus, correlates with short telomeres whereas retroviral-mediated restoration of hnRNP A1 expression results in telomeres with normal lengths. Expression of an amino-terminal fragment of hnRNP A1, known as UP1, also restores normal telomere length whereas only recombinant glutathione S-transferase (GST) - UP1 recovers telomerase activity from cell lysates in a pull-down assay.
21. Grabowski PJ: Splicing regulation in neurons: Tinkering with cell-specific control. Cell 1998, 92:709-712.
22. Mayeda A, Krainer AR: Regulation of alternative pre-mRNA splicing by hnRNP A1 and splicing factor SF2. Cell 1992, 68:365-375.
23. Mayeda A, Munroe SH, Xu R-M, Krainer AR: Distinct functions of the closely related tandem RNA-recognition motifs of hnRNP A1. RNA 1998, 4:1111-1123.
24. Zu K, Sikes ML, Beyer AL: Separable roles in vivo for the two RNA-binding domains of a Drosophila A1-hnRNP homolog. RNA 1998, 4:1585-1598.
25. Del Gatto-Konczak F, Olive M, Gesnel M-C, Breathnach R: hnRNP A1 recruited to an exon in vivo can function as an exon splicing silencer. Mol Cell Biol 1999, 19:251-260.
26. Chabot B, Blanchette M, Lapierre I, La Branche H: An intron element modulating 5′ splice site selection in the hnRNP A1 pre-mRNA interacts with hnRNP A1. Mol Cell Biol 1997, 17:1776-1786.
27. Hammond LE, Rudner DZ, Kanaar R, Rio DC: Mutations in the hrp48 gene, which encodes a Drosophila heterogeneous nuclear ribonucleoprotein particle protein, cause lethality and developmental defects and affect P-element third-intron splicing in vivo. Mol Cell Biol 1997, 17:7260-7267. A genetic approach is employed to elucidate the function of the Drosophila hrp48 protein which is related to vertebrate hnRNP A/B proteins. The hrp48 gene is essential and mutant flies that express low levels of hrp48 show eye and bristle defects. Examination of pre-mRNA splicing in vivo using a P-element reporter transgene supports the proposal that hrp48 is required to suppress splicing of the third intron in somatic tissues.
28. Modafferi EF, Black DL: A complex intronic splicing enhancer from the c-src pre-mRNA activates inclusion of a heterologous exon. Mol Cell Biol 1997, 17:6537-6545.
29. Min H, Turck CW, Nikolic JM, Black DL: A new regulatory protein, KSRP, mediates exon inclusion through an intronic splicing enhancer. Genes Dev 1997, 11:1023-1036.
30. Chou M-Y, Rooke N, Turck CW, Black DL: hnRNP H is a component of a splicing enhancer complex that activates a c-src alternative exon in neuronal cells. Mol Cell Biol 1999, 19:69-77. To elucidate cellular mechanisms involved in neural-specific alternative splicing, hnRNP H is identified as the second hnRNP component of a protein complex that binds to the intronic enhancer downstream of the c-src N1 exon. Efficient splicing of the N1 exon requires hnRNP H in vitro. This enhancer complex also contains hnRNP F, and hnRNPs F and H are shown to interact in vitro. Thus, interactions between multiple hnRNPs and RNA enhancer elements may be critical for splicing enhancer function.
31. Chan RC, Black DL: The polypyrimidine tract binding protein binds upstream of neural cell-specific c-src exon N1 to repress the splicing of the intron downstream. Mol Cell Biol 1997, 17:4667-4676. In non-neural cells, splicing of the c-src N1 exon is repressed. This repression requires CU-rich elements located in the polypyrimidine tract upstream of N1 that bind specifically to PTB/hnRNP I. Although competitor RNAs containing the repressor element derepress N1 splicing, addition of recombinant PTB/hnRNP I restores repression. In other systems, PTB/hnRNP I binding correlates with splicing repression of the proximal intron. In this case, PTB/hnRNP I represses splicing of the intron downstream of the N1 exon possibly by interacting with U1 snRNP bound at the N1 5′ splice site (ss) and inhibiting spliceosome formation.
32. A receptor γ2 is repressed in non-neural cells by four pyrimidine-rich repressor elements situated near the branch point of the upstream intron and within the exon itself. These repressor elements bind PTB/hnRNP I. Exon selection can be activated by addition of RNA competitors containing these repressor elements which results in dual activation of flanking introns. A repression model is proposed in which the three repressor elements in the upstream intron block U2 snRNP binding to the branch point while the exonic repressor blocks U1 snRNP binding to the downstream 5′ splice site (ss).
33. Zhang L, Liu W, Grabowski PJ: Coordinate repression of a trio of neuron-specific splicing events by the splicing regulator, PTB. RNA 1999, 5:117-130. The PTB/hnRNP I protein is shown to repress splicing of three different neural-specific exons while neural extracts show binding of CUG-BP/hNab50. The introns upstream of the clathrin light chain B exon EN and N-methyl-D-aspartate receptor NR1 subunit exon 5 contain overlapping repressor (UCUU) and enhancer (CUG) elements that bind to PTB/hnRNP I and CUG-BP respectively. These results suggest that hnRNPs may compete for intronic elements to either activate or repress adjacent exon splicing.
34. Lou H, Helfman DM, Gagel RF, Berget SM: Polypyrimidine tract binding protein positively regulates inclusion of an alternative 3′-terminal exon. Mol Cell Biol 1999, 19:78-85. The gene encoding calcitonin (CT) and the calcitonin gene-related peptide (CGRP) contains an alternative 3′-terminal exon (exon 4) that includes a polyadenylation site. Exon 4 is included in thyroid C cells, which express CT while neurons skip this exon to produce CGRP and use the downstream exon 6 poly(A) site. Pre-mRNA processing of CT/CGRP is controlled by polyadenylation through the action of a 127 nucleotide intronic enhancer positioned downstream of exon 4. A polypyrimidine tract within a core sequence of this enhancer binds PTB/hnRNP I, and increasing the level of this hnRNP in vivo results in increased exon 4 inclusion. Another PTB/hnRNP I binding site is within exon 4 near the polyadenylation signal. The results suggest dual functions for PTB/hnRNP I in blocking splicing factor recognition of the intronic enhancer while facilitating upstream site polyadenylation.
35. n triplet repeat RNA-binding protein and its expression in myotonic dystrophy. Nucleic Acids Res 1996, 24:4407-4414.
36. n expansion mutation causes an increase in the splicing activity of CUG-BP.
37. Moreira A, Takagaki Y, Brackenridge S, Wollerton M, Manley JL, Proudfoot NJ: The upstream sequence element of the C2 complement poly(A) signal activates mRNA 3′ end formation by two distinct mechanisms. Genes Dev 1998, 12:2522-2534. The C2 complement gene contains an upstream activation sequence (UAS) that enhances 3′-end cleavage and polyadenylation. This element binds PTB/hnRNP I and addition of recombinant PTB/hnRNP I activates cleavage but not polyadenylation, in vitro. This study provides additional evidence that hnRNPs have dual functions in splicing and 3′-end processing.
38. Bagga PS, Arhin GK, Wilusz J: DSEF-1 is a member of the hnRNP H family of RNA binding proteins and stimulates pre-mRNA cleavage and polyadenylation in vitro. Nucleic Acids Res 1998, 26:5343-5350.
39. Kessler MM, Henry MF, Shen E, Zhao J, Gross S, Silver PA, Moore CL: Hrp1p, a sequence-specific RNA-binding protein that shuttles between the nucleus and the cytoplasm, is required for mRNA 3′-end formation in yeast. Genes Dev 1997, 11:2545-2556. Pre-mRNA 3′-end processing in yeast requires several cleavage factors (CF IA, CF IB, CF II) and polyadenylation factors. This paper shows that Hrp1p (Nab4p) is the sole constituent of CF IB, and that Hrp1p is required for cleavage and polyadenylation in vitro. Mutant hrp1 strains show aberrant polyadenylation in vivo and are synthetically lethal with rna 14 and rna 15 (CF IA components). Evidence is presented that Hrp1p shuttles between the nucleus and cytoplasm suggesting a possible linkage between 3′-end formation and nucleocytoplasmic export of mRNAs.
40. Minvielle-Sebastia L, Beyer K, Krecic AM, Hector RE, Swanson MS, Keller W: Control of cleavage site selection during mRNA 3′ end formation by a yeast hnRNP. EMBO J 1998, 17:7454-7468. Evidence is presented that the yeast hnRNP Nab4p (Hrp1p) is not an essential cleavage factor in vitro or in vivo, but that it influences cleavage site selection in vitro. Using purified cleavage factors and an in vitro cleavage assay, Nab4p (Hrp1p) is shown to repress utilization of cryptic cleavage sites upstream of the major poly(A) addition site in a concentration-dependent manner. As Nab4p (Hrp1p) is structurally related to human hnRNP A1, these results suggest that these hnRNPs may facilitate alternative selection of endonucleolytic cleavage sites via a similar mechanism.
41. Ostareck DH, Ostareck-Lederer A, Wilm M, Thiele BJ, Mann M, Hentze MW: mRNA silencing in erythroid differentiation: hnRNP K and hnRNP E1 regulate 15-lipoxygenase translation from the 3′-end. Cell 1997, 89:597-606. This paper probes the role of hnRNPs as translational regulators. hnRNP K and PCBP-1 are identified as components of a erythroid 15-lipoxygenase mRNA binding activity associated with translational silencing. These proteins are associated with silenced LOX mRNA in vivo and they specifically regulate silencing both in vitro and in vivo. Intriguingly, these proteins appear to block 80S ribosome assembly and inhibit both cap-mediated and IRES-mediated translation.
42. Ostareck-Lederer A, Ostareck DH, Hentze MW: Cytoplasmic regulatory functions of the KH-domain proteins hnRNPs K and E1/E2. Trends Biochem Sci 1998, 23:409-411.
43. Collier B, Goobar-Larsson L, Sokolowski M, SChwartz S: Translational inhibition in vitro of human papillomavirus type 16 L2 mRNA mediated through interaction with heterogeneous ribonucleoprotein K and poly(rC)-binding proteins 1 and 2. J Biol Chem 1998, 273:22648-22656.
44. Rajagopalan LE, Westmark CJ, Jarzembowski JA, Malter JS: hnRNP C increases amyloid precursor protein (APP) production by stabilizing APP mRNA. Nucleic Acids Res 1998, 26:3418-3423.
45. Kiledjian M, Demaria CT, Brewer G, Novick K: Identification of AUF1 (heterogeneous nuclear ribonucleoprotein D) as a component of the α-globin mRNA stability complex. Mol Cell Biol 1997, 17:4870-4876. The purpose of this study was to further characterize the composition of the α-complex that binds to the human α-globin mRNA 3′UTR to confer stability. Using a known component of the α-complex αCP1 (PCBP-1), as bait in a two-hybrid screen for interacting proteins, the AUF1/hnRNP D protein is identified. The relative interaction of various hnRNP D isoforms with αCP1 and αCP2 indicates preferential binding of the D proteins to αCP1 whereas multiple D isoforms are present in α-complex preparations. These data, as well as earlier studies implicating AUF1/hnRNP D in promoting ARE-mediated mRNA decay [46], suggest that the hnRNP D proteins can function as either rapid decay or stabilizing factors depending on the mRNA binding substrate.
46. Demaria CT, Brewer G: AUF1 binding affinity to A+U-rich elements correlates with rapid mRNA degradation. J Biol Chem 1996, 271:12179-12184.
47. Shih S-C, Claffey KP: Regulation of human vascular endothelial growth factor mRNA stability in hypoxia by heterogeneous nuclear ribonucleoprotein L. J Biol Chem 1999, 274:1359-1365.
48. Myer VE, Fan XC, Steitz JA: Identification of HuR as a protein implicated in AUUUA-mediated mRNA decay. EMBO J 1997, 16:2130-2139.
49. Fan XC, Steitz JA: Overexpression of HuR, a nuclear-cytoplasmic shuttling protein, increases the in vivo stability of ARE-containing mRNAs. EMBO J 1998, 17:3448-3460. The question of whether HuR has a destabilizing or stabilizing effect on ARE-containing mRNAs is examined in vivo. The authors demonstrate that overexpression of HuR stabilizes ARE-containing mRNAs in transfected cells. Because it is generally believed that ARE-mediated mRNA decay occurs in the cytoplasm, the observation that HuR shuttles between the nucleus and cytoplasm provides at least one way to reconcile this apparent paradox. These authors suggest a model whereby HuR binds ARE-containing mRNAs in the nucleus and accompanies them to the cytoplasm to confer protection from degradation.
50. Peng SS-Y, Chen C-YA, Xu N, Shyu A-B: RNA stabilization by the AU-rich element binding protein, HuR, an ELAV protein. EMBO J 1998, 17:3461-3470. The role of HuR in ARE-mediated mRNA decay in vivo is addressed. Ectopic expression of HuR has differential effects on various ARE-containing mRNAs and HuR appears to primarily affect decay of the mRNA body and not deadenylation. HuR accumulates in the cytoplasm of cells in the absence of RNA polymerase II transcription, consistent with the observed increase in the inhibition of ARE-mediated destabilization. The authors propose that ARE-mediated decay may be modulated by alterations in the subcellular distribution of ELAV proteins during cell growth and differentiation.
51. Fan XC, Steitz JA: HNS, a nuclear-cytoplasmic shuttling sequence in HuR. Proc Natl Acad Sci USA 1998, 95:15293-15298.
52. Czaplinski K, Ruiz-Echevarria MJ, Peltz SW: Should we kill the messenger? the role of the surveillance complex in regulating translation termination. Bioessays 1999, in press.
53. Leffers H, Dejgaard K, Celis JE: Characterisation of two major cellular poly(rC)-binding human proteins, each containing three K-homologous (KH) domains. Eur J Biochem 1995, 230:447-453.
54. Gamberi C, Izaurralde E, Beisel C, Mattaj IW: Interaction between the human nuclear cap-binding protein complex and hnRNP F. Mol Cell Biol 1997, 17:2587-2597.
55. Liu X, Mertz JE: hnRNP L binds a cis-acting RNA sequence element that enables intron-independent gene expression. Genes Dev 1995, 9:1766-1780.
56. Gattoni R, Mahé D, Mähl P, Fischer N, Mattei M-G, Stévenin J, Fuchs J-P: The human hnRNP-M proteins: Structure and relation with early heat shock-induced splicing arrest and chromosome mapping. Nucleic Acids Res 1996,24:2535-2542.
57. Calvio C, Neubauer G, Mann M, Lamond AI: Identification of hnRNP P2 as TLS/FUS using electrospray mass spectrometry. RNA 1995, 1:724-733.
58. Hassfeld W, Chan EKL, Mathison DA, Portman D, Dreyfuss G, Steiner G, Tan EM: Molecular definition of heterogeneous nuclear ribonucleoprotein R (hnRNP R) using autoimmune antibody: Immunological relationship with hnRNP P. Nucleic Acids Res 1998, 26:439-445.
59. Myer VE, Steitz JA: Isolation and characterization of a novel low abundance hnRNP protein: A0. RNA 1995, 1:171-182.
60. Pérez I, Lin C-H, McAfee JG, Patton JG: Mutation of PTB binding sites causes misregulation of alternative 3′ splice site selection in vivo. RNA 1997, 34:764-778.
61. Valentini SR, Weiss VH, Silver PA: Arginine methylation and binding of Hrp1p to the efficiency element for mRNA 3′-end formation. RNA 1999, 5:272-280.
62. Chen S, Hyman LE: A specific RNA-protein interaction at yeast polyadenylation efficiency elements. Nucleic Acids Res 1998, 26:4965-4974.