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The role of LARP1 in translation and beyond

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Abstract The LARP1 proteins form an evolutionarily homogeneous subgroup of the eukaryotic superfamily of La‐Motif (LAM) containing factors. Members of the LARP1 family are found in most protists, fungi, plants, and animals. We review here evidence suggesting that LARP1 are key versatile messenger RNA (mRNA)‐binding proteins involved in regulating important biological processes such as gametogenesis, embryogenesis, sex determination, and cell division in animals, as well as acclimation to stress in yeasts and plants. LARP1 proteins perform all these essential tasks likely by binding to key mRNAs and regulating their stability and/or translation. In human, the impact of LARP1 over cell division and proliferation is potentially under the control of the TORC1 complex. We review data suggesting that LARP1 is a direct target of this master signaling hub. TOR‐dependent LARP1 phosphorylation could specifically enhance the translation of TOP mRNAs providing a way to promote translation, growth, and proliferation. Consequently, LARP1 is found to be significantly upregulated in many malignant cell types. In plants, LARP1 was found to act as a cofactor of the heat‐induced mRNA degradation process, an essential acclimation strategy leading to the degradation of more than 4500 mRNAs coding for growth and development housekeeping functions. In Saccharomyces cerevisiae, the LARP1 proteins (Slf1p and Sro9p) are important, among other things, for copper resistance and oxidative stress survival. LARP1 proteins are therefore emerging as critical ancient mRNA‐binding factors that evolved common as well as specific targets and regulatory functions in all eukaryotic lineages. WIREs RNA 2015, 6:399–417. doi: 10.1002/wrna.1282 This article is categorized under: Translation > Translation Mechanisms RNA Turnover and Surveillance > Regulation of RNA Stability
Phylogenetic relationship and domain organizations among La‐Motif containing proteins (Reprinted with permission from Ref . Copyright 2009 Cold Spring Harbor Laboratory Press). La‐Motif proteins fall into five evolutionarily conserved families. Members of a given family share conserved domain organization. As for the genuine La proteins, the LAM‐RRM1 or La‐Module is found in every LARP subgroup. With the exception of the LARP7 family, which has a canonical RRM1, other LARP families display specific variant RRM1, labeled RRM‐L (RRM‐Like). Additional conserved motifs, specific to each La and Related subfamilies, can also be found. The LARP1 proteins display a highly conserved C‐terminus called DM15. The LARP4 and higher plant LARP6 have a PAM2 domain, a small structured region that directly fits into the MLLE domain found at the C‐terminus of the Poly(A) Binding Proteins (PABP). LARP proteins displaying a PAM2 domain display a divergent LAM (labeled with vertical black bars). The LARP6 proteins also display a short conserved domain named LSA (for LAM and S1 Associated). The genuine La and LARP7 proteins have a second non‐canonical C‐terminal RRM, labeled RRM2.
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Model for S. cerevisiae Slf1p and Sro9p function. Slf1p and Sro9p are mRNA‐binding proteins with distinct and overlapping functions. Sro9p, but not Slf1p was found to shuttle between nucleus and cytoplasm and to associate to mRNPs co‐translationally. Sro9p is proposed to promote pol II transcription and/or cytoplasmic stability of its mRNA targets. Sro9p and Slf1p are proposed to cooperate to promote expression (through mRNA stabilization and/or translation stimulation) of protein synthesis components. Slf1p specifically stabilizes mRNAs coding for copper detoxification factors and stimulates translation of oxidative stress response genes in the context of oxidative stress. Slf1p could directly bind to a 3′‐UTR located, 21‐nt long AU rich element shared by oxidative stress response mRNAs enriched in the Slf1p bound fraction. Sro9p is required for yeast survival to copper and H202 exposure, suggesting that it might also be required for stress acclimation but through a distinct molecular mechanism.
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Phylogenetic analysis of fungi LARP1 proteins based on the alignment of their LAM. Two fungi genuine La proteins (LHP1 form S. cerevisiae and SpLa1 S. pombe) are used as outgroup. Selected informative statistical supports (approximate likelihood‐ratio test (aLRT) data) are indicated. The common names (ScSLF1, ScSRO9) for the two S. cerevisiae LARP1 are used. For all other LARP1, a species code name is indicated followed by a code for its classification (see below and Figure ). LARP1 from species in the same subphylum as S. cerevisiae are in red. The species codes are the following: Agabi: Agaricus bisporus, Agahy: Agaricostilbum hyphaenes, Amath: Amanita thiersii, Artol: Arthrobotrys oligospora, Aspni: Aspergillus niger, Aspwe: Aspergillus wentii, Aurpu: Aureobasidium pullulans, Babin: Babjeviella inositovora, Botci: Botrytis cinerea, Calvi: Calocera viscosa, Chove: Choiromyces venosus, Clagr: Cladonia grayi, Cryvi: Cryptococcus vishniacii, Daequ: Daedalea quercina, Exigl: Exidia glandulosa, Exova: Exobasidium vaccinii, Gymau: Gymnascella aurantiaca, Hetpy: Heterogastridium pycnidioideum, Hypbu: Hyphopichia burtonii, Hypsu: Hypholoma sublateritium, Leumo: Leucogyrophana Mollusca, Lipst: Lipomyces starkeyi, Mixos: Mixia osmundae, Monha: Monacrosporium haptotylum, Neopa: Neofusicoccum parvum, Neucr: Neurospora crassa, Pneji: Pneumocystis jirovecii, Pleos: Pleurotus ostreatus, Polar: Polyporus arcularius, Psehu: Pseudozyma hubeiensis, Rhoba: Rhodotorula sp, Saico: Saitoella complicate, Schpo: Schizosaccharomyces pombe, Sclsc: Sclerotinia sclerotiorum, Spoli: Sporobolomyces linderae, Spore: Sporisorium reilianum, Spoth: Tapde: Taphrina deformans, Theau: Thermoascus aurantiacus, Trepe: Trematosphaeria pertusa, Trias: Trichoderma asperellum, Spoth: Sporotrichum thermophile, Wilmi: Wilcoxina mikolae, Xylhe: Xylona heveae, Yarli: Yarrowia lipolytica. The classification codes are the following: APD: Ascomycota Pezizomycotina Dothideomycetes, APE: Ascomycota Pezizomycotina Eurotiomycetes, APLEC: Ascomycota Pezizomycotina Lecanoromycetes, APLEO: Ascomycota Pezizomycotina Leeotiomycetes, APO: Ascomycota Pezizomycotina Orbiliomycetes, APP: Ascomycota Pezizomycotina Pezizomycetes, APS: Ascomycota Pezizomycotina Sordariomycetes, APX: Ascomycota Pezizomycotina Xylonomycetes, AS: Ascomycota Saccharomycotinia, AT: Ascomycota Taphrinomycotina, BA: Basidiomycota Agaricomycotina, BP: Basidiomycota Pucciniomycotina, BU: Basidiomycota Ustilaginomycotina.
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Relationships between major groups of fungi and corresponding structural organization of LARP1 proteins. There is no LARP1 protein in species from the Microsporia phylum. Since a genome of a basal Zoopagomycotina species has yet to be sequenced, the presence of LARP1 in this subphylum is uncertain. Since the RRM‐Like in the LARP1 family is not conserved at the primary sequence level, it is not known if the complete fungi LARP1 proteins also present a La‐module. The figure of relationships between major groups of fungi is from the MycoCosm web site.
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Model for Arabidopsis thaliana LARP1 function in response to heat stress. Heat stress triggers the accelerated decay of several thousand mRNAs coding for housekeeping/growth related functions. These transcripts are degraded by a 5′‐directed mechanism, catalyzed by XRN4 following a decapping step. Arabidopsis LARP1 is a cofactor of this heat‐induced mRNA decay process. In response to heat, it forms a complex with XRN4 and acts to target this enzyme to polysomes, one of the heat triggered mRNA decay sites.
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Model for Human LARP1 role in the mTOR pathway. (a) mTOR‐dependent phosphorylation of LARP1 would stimulate TOP‐mRNAs translation and protect them from decay. LARP1 association with the cap‐binding complex is dependent upon mTOR activity and blocked by eIF4E‐BP association with eIF4E (Refs ; Lahr et al., manuscript in preparation), (b) LARP1 is proposed to bind to the mTOR transcript, possibly at its 3′‐UTR, and would act to stabilize it in the cytoplasm.
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Structural features of the LARP1 proteins. (a) Schematic representation of the two types of LARP1 proteins. (b) Representation of the structural arrangement of LARP1 proteins from Drosophila melanogaster (NP_733244), C. elegans (NP_001040868), H. sapiens (LAR1a: NP_056130, LARP1b (formely LARP2): NP_060548, LARP1c: XP_001715526), A. thaliana (LARP1a: AT5G21160; LARP1b: AT5g66100; LARP1c: AT4G35890), S. cerevisiae (Slf1p:YDR515W and Sro9p:YCL037C) and S. pombe (SpLARP: SPAC1527.03). The La‐Motif (LAM) is in red, RRM_L5 in blue and the DM15 domain represented by three colored boxes corresponding to the A, B and C motifs bordered by conserved boxes and 2 in gray. The S. cerevisiae proteins were proposed to have two conserved patched (1 and 2, represented in green boxes), a lysine (K)‐rich and an asparagine (N)‐rich region located upstream to their LAM.
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