mRNA localization as a rheostat to regulate subcellular gene expression

Advanced Review

Nevraj S. Kejiou, Alexander F. Palazzo

Published Online: Jan 24 2017

DOI: 10.1002/wrna.1416

Full article on Wiley Online Library: HTML PDF

Can't access this content? Tell your librarian.

It is currently believed that certain messenger RNAs (mRNAs) are localized to distinct subcellular regions to efficiently target their encoded proteins. However, this simplistic model does not explain why in certain scenarios mRNA localization is dispensable for proper protein distribution. In other cases, mRNA localization is accompanied by translational silencing and degradation by the localization machinery. Here we propose that in certain scenarios mRNAs are localized so that they can either be stabilized and translated, or silenced and degraded, in response to the needs of the subcellular locale. In these cases, the localized mRNA, and its cadre of associated factors, act as a rheostat that regulates protein production and/or mRNA stability in response to the needs of its immediate subcellular environment. WIREs RNA 2017, 8:e1416. doi: 10.1002/wrna.1416 This article is categorized under: Translation > Translation Regulation RNA Export and Localization > RNA Localization RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms

Localized translation as a means to regulate long‐term potentiation. Messenger ribonuclear protein (mRNP) complexes travel along the dendrite in a translationally silenced state. Upon synaptic excitation, these mRNPs are recruited, and become anchored to the base of the activated PSD, and are translated into proteins. Importantly, activated mRNAs are relatively static and do not diffuse to nearby PSDs. Translation of some PSD‐recruited mRNAs activates their destruction by NMD (see Box ), further restricting protein expression. The restricted expression of proteins stabilize the activated PSD while preventing the stabilization of nearby nonstimulated PSDs. This differential regulation of mRNA translation forms the basis of long‐term potentiation (LTP).

[ Normal View | Magnified View ]

Local regulation of CLB2 mRNA translation in the bud of S. cerevisiae. CLB2 mRNA is transported to the bud along actin cables by the She machinery. Its translation in the bud is likely responsive to bud‐specific conditions, and controls mitotic entry. Then CLB2 is degraded in TAM bodies and this regulates mitotic exit.

[ Normal View | Magnified View ]

Puf3p acts as a local or a global regulator of mitochondrial‐associated nuclear encoded mRNA. Puf3p translationally represses mRNAs coding for mitochondrial proteins at the surface of the mitochondria. Reduction of intracellular glucose level induces the phosphorylation of Puf3p, allowing the translation of Puf3p‐associated mRNA. It is unclear if these mRNAs are released and translated in the vicinity of mitochondria or if they become associated with mitochondrial‐tethered ribosomes. In contrast to this global regulation, local mitochondrial stress, such as ROS‐mediated damage, relieves Puf3p‐dependent repression of mRNAs allowing translation in the vicinity or on the surface of the mitochondrion thereby promoting mitochondrial repair and biogenesis. Severe or prolonged local mitochondrial stress induces Puf3p to sequester and repress mRNAs, which ultimately targets the destruction of the mitochondrion by mitophagy.

[ Normal View | Magnified View ]

References

Lécuyer, E, Yoshida, H, Parthasarathy, N, Alm, C, Babak, T, Cerovina, T, Hughes, TR, Tomancak, P, Krause, HM. Global analysis of mRNA localization reveals a prominent role in organizing cellular architecture and function. Cell 2007, 131:174–187.
Wilk, R, Hu, J, Blotsky, D, Krause, HM. Diverse and pervasive subcellular distributions for both coding and long noncoding RNAs. Genes Dev 2016, 30:594–609.
Casolari, JM, Thompson, MA, Salzman, J, Champion, LM, Moerner, WE, Brown, PO. Widespread mRNA association with cytoskeletal motor proteins and identification and dynamics of myosin‐associated mRNAs in S. cerevisiae. PLoS One 2012, 7:e31912.
Cody, NAL, Iampietro, C, Lécuyer, E. The many functions of mRNA localization during normal development and disease: from pillar to post. WIREs Dev Biol 2013, 2:781–796.
Steward, O, Levy, WB. Preferential localization of polyribosomes under the base of dendritic spines in granule cells of the dentate gyrus. J Neurosci 1982, 2:284–291.
Burgin, KE, Waxham, MN, Rickling, S, Westgate, SA, Mobley, WC, Kelly, PT. In situ hybridization histochemistry of Ca2+/calmodulin‐dependent protein kinase in developing rat brain. J Neurosci 1990, 10:1788–1798.
Kacharmina, JE, Job, C, Crino, P, Eberwine, J. Stimulation of glutamate receptor protein synthesis and membrane insertion within isolated neuronal dendrites. Proc Natl Acad Sci USA 2000, 97:11545–11550.
Tiruchinapalli, DM, Oleynikov, Y, Kelic, S, Shenoy, SM, Hartley, A, Stanton, PK, Singer, RH, Bassell, GJ. Activity‐dependent trafficking and dynamic localization of zipcode binding protein 1 and β‐actin mRNA in dendrites and spines of hippocampal neurons. J Neurosci 2003, 23:3251–3261.
Link, W, Konietzko, U, Kauselmann, G, Krug, M, Schwanke, B, Frey, U, Kuhl, D. Somatodendritic expression of an immediate early gene is regulated by synaptic activity. Proc Natl Acad Sci USA 1995, 92:5734–5738.
Miller, S, Yasuda, M, Coats, JK, Jones, Y, Martone, ME, Mayford, M. Disruption of dendritic translation of CaMKIIα impairs stabilization of synaptic plasticity and memory consolidation. Neuron 2002, 36:507–519.
Sheng, M, Erturk, A. Long‐term depression: a cell biological view. Philos Trans R Soc B Biol Sci 2013, 369:20130138.
Liu, H‐H, Cline, HT. Fragile X mental retardation protein is required to maintain visual conditioning‐induced behavioral plasticity by limiting local protein synthesis. J Neurosci 2016, 36:7325–7339.
Pfeiffer, BE, Huber, KM. Fragile x mental retardation protein induces synapse loss through acute postsynaptic translational regulation. J Neurosci 2007, 27:3120–3130.
Fernandez‐Moya, SM, Bauer, KE, Kiebler, MA. Meet the players: local translation at the synapse. Front Mol Neurosci 2014, 7:84
Vlatkovic, I, Schuman, EM. Dendrites. Oxford, US: Oxford University Press; 2016, 129–158.
Giorgi, C, Yeo, GW, Stone, ME, Katz, DB, Burge, C, Turrigiano, G, Moore, MJ. The EJC factor eIF4AIII modulates synaptic strength and neuronal protein expression. Cell 2007, 130:179–191.
Farris, S, Lewandowski, G, Cox, CD, Steward, O. Selective localization of arc mRNA in dendrites involves activity‐ and translation‐dependent mRNA degradation. J Neurosci 2014, 34:4481–4493.
Yoon, YJ, Wu, B, Buxbaum, AR, Das, S, Tsai, A, English, BP, Grimm, JB, Lavis, LD, Singer, RH. Glutamate‐induced RNA localization and translation in neurons. Proc Natl Acad Sci 2016, 113:E6877–6886.
Huang, L, Wilkinson, MF. Regulation of nonsense‐mediated mRNA decay. WIREs RNA 2012, 3:807–828.
Lykke‐Andersen, S, Jensen, TH. Nonsense‐mediated mRNA decay: an intricate machinery that shapes transcriptomes. Nat Rev Mol Cell Biol 2015, 16:665–677.
Karousis, ED, Nasif, S, Mühlemann, O. Nonsense‐mediated mRNA decay: novel mechanistic insights and biological impact: Nonsense‐mediated mRNA decay. WIREs RNA 2016, 7:661–682.
Le Hir, H, Izaurralde, E, Maquat, LE, Moore, MJ. The spliceosome deposits multiple proteins 20–24 nucleotides upstream of mRNA exon‐exon junctions. EMBO J 2000, 19:6860–6869.
Toma, KG, Rebbapragada, I, Durand, S, Lykke‐Andersen, J. Identification of elements in human long 3′ UTRs that inhibit nonsense‐mediated decay. RNA 2015, 21:887–897.
Shen, K, Meyer, T. Dynamic control of CaMKII translocation and localization in hippocampal neurons by NMDA receptor stimulation. Science 1999, 284:162–167.
Lemieux, M, Labrecque, S, Tardif, C, Labrie‐Dion, É, LeBel, É, De Koninck, P. Translocation of CaMKII to dendritic microtubules supports the plasticity of local synapses. J Cell Biol 2012, 198:1055–1073.
Williams, CC, Jan, CH, Weissman, JS. Targeting and plasticity of mitochondrial proteins revealed by proximity‐specific ribosome profiling. Science 2014, 346:748–751.
Marc, P, Margeot, A, Devaux, F, Blugeon, C, Corral‐Debrinski, M, Jacq, C. Genome‐wide analysis of mRNAs targeted to yeast mitochondria. EMBO Rep 2002, 3:159–164.
Gerber, AP, Herschlag, D, Brown, PO. Extensive association of functionally and cytotopically related mRNAs with Puf family RNA‐binding proteins in yeast. PLoS Biol 2004, 2:E79.
García‐Rodríguez, LJ, Gay, AC, Pon, LA. Puf3p, a Pumilio family RNA binding protein, localizes to mitochondria and regulates mitochondrial biogenesis and motility in budding yeast. J Cell Biol 2007, 176:197–207.
Saint‐Georges, Y, Garcia, M, Delaveau, T, Jourdren, L, Le Crom, S, Lemoine, S, Tanty, V, Devaux, F, Jacq, C. Yeast mitochondrial biogenesis: a role for the PUF RNA‐binding protein Puf3p in mRNA localization. PLoS One 2008, 3:e2293.
Olivas, W. The Puf3 protein is a transcript‐specific regulator of mRNA degradation in yeast. EMBO J 2000, 19:6602–6611.
Houshmandi, SS, Olivas, WM. Yeast Puf3 mutants reveal the complexity of Puf‐RNA binding and identify a loop required for regulation of mRNA decay. RNA NY 2005, 11:1655–1666.
Chatenay‐Lapointe, M, Shadel, GS. Repression of mitochondrial translation, respiration and a metabolic cycle‐regulated gene, SLF1, by the yeast pumilio‐family protein Puf3p. PLoS One 2011, 6:e20441.
Lee, C‐D, Tu, BP. Glucose‐regulated phosphorylation of the PUF protein Puf3 regulates the translational fate of its bound mrnas and association with RNA granules. Cell Rep 2015, 11:1638–1650.
Miller, MA, Russo, J, Fischer, AD, Lopez Leban, FA, Olivas, WM. Carbon source‐dependent alteration of Puf3p activity mediates rapid changes in the stabilities of mRNAs involved in mitochondrial function. Nucleic Acids Res 2014, 42:3954–3970.
Kedersha, N, Stoecklin, G, Ayodele, M, Yacono, P, Lykke‐Andersen, J, Fritzler, MJ, Scheuner, D, Kaufman, RJ, Golan, DE, Anderson, P. Stress granules and processing bodies are dynamically linked sites of mRNP remodeling. J Cell Biol 2005, 169:871–884.
Rowe, W, Kershaw, CJ, Castelli, LM, Costello, JL, Ashe, MP, Grant, CM, Sims, PFG, Pavitt, GD, Hubbard, SJ. Puf3p induces translational repression of genes linked to oxidative stress. Nucleic Acids Res 2014, 42:1026–1041.
Verma‐Gaur, J, Qu, Y, Harrison, PF, Lo, TL, Quenault, T, Dagley, MJ, Bellousoff, M, Powell, DR, Beilharz, TH, Traven, A. Integration of posttranscriptional gene networks into metabolic adaptation and biofilm maturation in Candida albicans. PLoS Genet 2015, 11:e1005590.
Gadir, N, Haim‐Vilmovsky, L, Kraut‐Cohen, J, Gerst, JE. Localization of mRNAs coding for mitochondrial proteins in the yeast Saccharomyces cerevisiae. RNA NY 2011, 17:1551–1565.
Garcia, M, Delaveau, T, Goussard, S, Jacq, C. Mitochondrial presequence and open reading frame mediate asymmetric localization of messenger RNA. EMBO Rep 2010, 11:285–291.
Mathews, DH, Disney, MD, Childs, JL, Schroeder, SJ, Zuker, M, Turner, DH. Incorporating chemical modification constraints into a dynamic programming algorithm for prediction of RNA secondary structure. Proc Natl Acad Sci USA 2004, 101:7287–7292.
Wang, Y, Nartiss, Y, Steipe, B, McQuibban, GA, Kim, PK. ROS‐induced mitochondrial depolarization initiates PARK2/PARKIN‐dependent mitochondrial degradation by autophagy. Autophagy 2012, 8:1462–1476.
Böckler, S, Westermann, B. Mitochondrial ER contacts are crucial for mitophagy in yeast. Dev Cell 2014, 28:450–458.
Huh, W‐K, Falvo, JV, Gerke, LC, Carroll, AS, Howson, RW, Weissman, JS, O`Shea, EK. Global analysis of protein localization in budding yeast. Nature 2003, 425:686–691.
Eliyahu, E, Pnueli, L, Melamed, D, Scherrer, T, Gerber, AP, Pines, O, Rapaport, D, Arava, Y. Tom20 mediates localization of mRNAs to mitochondria in a translation‐dependent manner. Mol Cell Biol 2010, 30:284–294.
Eliyahu, E, Lesnik, C, Arava, Y. The protein chaperone Ssa1 affects mRNA localization to the mitochondria. FEBS Lett 2012, 586:64–69.
Quenault, T, Lithgow, T, Traven, A. PUF proteins: repression, activation and mRNA localization. Trends Cell Biol 2011, 21:104–112.
Twig, G, Elorza, A, Molina, AJA, Mohamed, H, Wikstrom, JD, Walzer, G, Stiles, L, Haigh, SE, Katz, S, Las, G, et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 2008, 27:433–446.
Twig, G, Shirihai, OS. The interplay between mitochondrial dynamics and mitophagy. Antioxid Redox Signal 2011, 14:1939–1951.
Gehrke, S, Wu, Z, Klinkenberg, M, Sun, Y, Auburger, G, Guo, S, Lu, B. PINK1 and parkin control localized translation of respiratory chain component mrnas on mitochondria outer membrane. Cell Metab 2015, 21:95–108.
Long, RM, Singer, RH, Meng, X, Gonzalez, I, Nasmyth, K, Jansen, RP. Mating type switching in yeast controlled by asymmetric localization of ASH1 mRNA. Science 1997, 277:383–387.
Takizawa, PA, Sil, A, Swedlow, JR, Herskowitz, I, Vale, RD. Actin‐dependent localization of an RNA encoding a cell‐fate determinant in yeast. Nature 1997, 389:90–93.
Jansen, R‐P, Dowzer, C, Michaelis, C, Galova, M, Nasmyth, K. Mother cell–specific ho expression in budding yeast depends on the unconventional myosin Myo4p and other cytoplasmic proteins. Cell 1996, 84:687–697.
Böhl, F, Kruse, C, Frank, A, Ferring, D, Jansen, RP. She2p, a novel RNA‐binding protein tethers ASH1 mRNA to the Myo4p myosin motor via She3p. EMBO J 2000, 19:5514–5524.
Long, RM, Gu, W, Lorimer, E, Singer, RH, Chartrand, P. She2p is a novel RNA‐binding protein that recruits the Myo4p‐She3p complex to ASH1 mRNA. EMBO J 2000, 19:6592–6601.
Schmid, M, Jaedicke, A, Du, T‐G, Jansen, R‐P. Coordination of endoplasmic reticulum and mRNA localization to the yeast bud. Curr Biol 2006, 16:1538–1543.
Aronov, S, Gelin‐Licht, R, Zipor, G, Haim, L, Safran, E, Gerst, JE. mRNAs encoding polarity and exocytosis factors are cotransported with the cortical endoplasmic reticulum to the incipient bud in Saccharomyces cerevisiae. Mol Cell Biol 2007, 27:3441–3455.
Shepard, KA, Gerber, AP, Jambhekar, A, Takizawa, PA, Brown, PO, Herschlag, D, DeRisi, JL, Vale, RD. Widespread cytoplasmic mRNA transport in yeast: identification of 22 bud‐localized transcripts using DNA microarray analysis. Proc Natl Acad Sci USA 2003, 100:11429–11434.
Takizawa, PA, DeRisi, JL, Wilhelm, JE, Vale, RD. Plasma membrane compartmentalization in yeast by messenger RNA transport and a septin diffusion barrier. Science 2000, 290:341–344.
Wolf, W, Kilic, A, Schrul, B, Lorenz, H, Schwappach, B, Seedorf, M. Yeast Ist2 recruits the endoplasmic reticulum to the plasma membrane and creates a ribosome‐free membrane microcompartment. PLoS One 2012, 7:e39703.
Manford, AG, Stefan, CJ, Yuan, HL, Macgurn, JA, Emr, SD. ER‐to‐plasma membrane tethering proteins regulate cell signaling and ER morphology. Dev Cell 2012, 23:1129–1140.
Surana, U, Robitsch, H, Price, C, Schuster, T, Fitch, I, Futcher, AB, Nasmyth, K. The role of CDC28 and cyclins during mitosis in the budding yeast S. cerevisiae. Cell 1991, 65:145–161.
Genz, C, Fundakowski, J, Hermesh, O, Schmid, M, Jansen, R‐P. Association of the yeast RNA‐binding protein She2p with the tubular endoplasmic reticulum depends on membrane curvature. J Biol Chem 2013, 288:32384–32393.
Cai, T, Aulds, J, Gill, T, Cerio, M, Schmitt, ME. The Saccharomyces cerevisiae RNase mitochondrial RNA processing is critical for cell cycle progression at the end of mitosis. Genetics 2002, 161:1029–1042.
Gill, T, Cai, T, Aulds, J, Wierzbicki, S, Schmitt, ME. RNase MRP cleaves the CLB2 mRNA to promote cell cycle progression: novel method of mRNA degradation. Mol Cell Biol 2004, 24:945–953.
Gill, T, Aulds, J, Schmitt, ME. A specialized processing body that is temporally and asymmetrically regulated during the cell cycle in Saccharomyces cerevisiae. J Cell Biol 2006, 173:35–45.
Spiesser, TW, Kühn, C, Krantz, M, Klipp, E. Bud‐localization of CLB2 mRNA can constitute a growth rate dependent daughter sizer. PLoS Comput Biol 2015, 11:e1004223.
Cui, XA, Zhang, H, Ilan, L, Liu, AX, Kharchuk, I, Palazzo, AF. mRNA encoding Sec61β, a tail‐anchored protein, is localized on the endoplasmic reticulum. J Cell Sci 2015, 128:3398–3410.
Kutay, U, Hartmann, E, Rapoport, TA. A class of membrane proteins with a C‐terminal anchor. Trends Cell Biol 1993, 3:72–75.
Kutay, U, Ahnert‐Hilger, G, Hartmann, E, Wiedenmann, B, Rapoport, TA. Transport route for synaptobrevin via a novel pathway of insertion into the endoplasmic reticulum membrane. EMBO J 1995, 14:217–223.
Cui, XA, Palazzo, AF. Localization of mRNAs to the endoplasmic reticulum. WIREs RNA 2014, 5:481–492.
Chen, Q, Jagannathan, S, Reid, DW, Zheng, T, Nicchitta, CV. Hierarchical regulation of mRNA partitioning between the cytoplasm and the endoplasmic reticulum of mammalian cells. Mol Biol Cell 2011, 22:2646–2658.
Cui, XA, Zhang, H, Palazzo, AF. p180 promotes the ribosome‐independent localization of a subset of mRNA to the endoplasmic reticulum. PLoS Biol 2012, 10:e1001336.
Cui, XA, Zhang, Y, Hong, SJ, Palazzo, AF. Identification of a region within the placental alkaline phosphatase mRNA that mediates p180‐dependent targeting to the endoplasmic reticulum. J Biol Chem 2013, 288:29633–29641.
Walter, P, Ron, D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 2011, 334:1081–1086.
Gaddam, D, Stevens, N, Hollien, J. Comparison of mRNA localization and regulation during endoplasmic reticulum stress in Drosophila cells. Mol Biol Cell 2013, 24:14–20.
Wilk, R, Hu, J, Krause, HM. Spatial profiling of nuclear receptor transcription patterns over the course of Drosophila development. G3 Bethesda MD 2013, 3:1177–1189.
Zipor, G, Haim‐Vilmovsky, L, Gelin‐Licht, R, Gadir, N, Brocard, C, Gerst, JE. Localization of mRNAs coding for peroxisomal proteins in the yeast, Saccharomyces cerevisiae. Proc Natl Acad Sci USA 2009, 106:19848–19853.
Haimovich, G, Cohen‐Zontag, O, Gerst, JE. A role for mRNA trafficking and localized translation in peroxisome biogenesis and function? Biochim Biophys Acta 2016, 1863:911–921.
Gu, W, Pan, F, Zhang, H, Bassell, GJ, Singer, RH. A predominantly nuclear protein affecting cytoplasmic localization of β‐actin mRNA in fibroblasts and neurons. J Cell Biol 2002, 156:41–51.
Sharp, JA, Plant, JJ, Ohsumi, TK, Borowsky, M, Blower, MD. Functional analysis of the microtubule‐interacting transcriptome. Mol Biol Cell 2011, 22:4312–4323.

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

mRNA localization as a rheostat to regulate subcellular gene expression

Related Articles

Browse by Topic

Access to this WIREs title is by subscription only.

The latest WIREs articles in your inbox