RTN3 Is a Novel Cold-Induced Protein and Mediates Neuroprotective Effects of RBM3

Overview

Journal Curr Biol

Publisher Cell Press

Specialty Biology

Date 2017 Feb 28

PMID 28238655

Citations 42

Authors

Amandine Bastide

Diego Peretti

John R P Knight

Stefano Grosso

Ruth V Spriggs

Xavier Pichon

Thomas Sbarrato

Anne Roobol

Jo Roobol

Davide Vito

Martin Bushell

Tobias von der Haar

C Mark Smales

Giovanna R Mallucci

Anne E Willis

Affiliations

Soon will be listed here.

Abstract

Cooling and hypothermia are profoundly neuroprotective, mediated, at least in part, by the cold shock protein, RBM3. However, the neuroprotective effector proteins induced by RBM3 and the mechanisms by which mRNAs encoding cold shock proteins escape cooling-induced translational repression are unknown. Here, we show that cooling induces reprogramming of the translatome, including the upregulation of a new cold shock protein, RTN3, a reticulon protein implicated in synapse formation. We report that this has two mechanistic components. Thus, RTN3 both evades cooling-induced translational elongation repression and is also bound by RBM3, which drives the increased expression of RTN3. In mice, knockdown of RTN3 expression eliminated cooling-induced neuroprotection. However, lentivirally mediated RTN3 overexpression prevented synaptic loss and cognitive deficits in a mouse model of neurodegeneration, downstream and independently of RBM3. We conclude that RTN3 expression is a mediator of RBM3-induced neuroprotection, controlled by novel mechanisms of escape from translational inhibition on cooling.

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References

van der Worp H, Sena E, Donnan G, Howells D, Macleod M . Hypothermia in animal models of acute ischaemic stroke: a systematic review and meta-analysis. Brain. 2007; 130(Pt 12):3063-74. DOI: 10.1093/brain/awm083. View

Tong G, Endersfelder S, Rosenthal L, Wollersheim S, Sauer I, Buhrer C . Effects of moderate and deep hypothermia on RNA-binding proteins RBM3 and CIRP expressions in murine hippocampal brain slices. Brain Res. 2013; 1504:74-84. DOI: 10.1016/j.brainres.2013.01.041. View

Matsuzaki F, Shirane M, Matsumoto M, Nakayama K . Protrudin serves as an adaptor molecule that connects KIF5 and its cargoes in vesicular transport during process formation. Mol Biol Cell. 2011; 22(23):4602-20. PMC: 3226478. DOI: 10.1091/mbc.E11-01-0068. View

Chip S, Zelmer A, Ogunshola O, Felderhoff-Mueser U, Nitsch C, Buhrer C . The RNA-binding protein RBM3 is involved in hypothermia induced neuroprotection. Neurobiol Dis. 2011; 43(2):388-96. DOI: 10.1016/j.nbd.2011.04.010. View

Roobol A, Carden M, Newsam R, Smales C . Biochemical insights into the mechanisms central to the response of mammalian cells to cold stress and subsequent rewarming. FEBS J. 2008; 276(1):286-302. DOI: 10.1111/j.1742-4658.2008.06781.x. View

Jena A, Romley J, Newton-Cheh C, Noseworthy P . Therapeutic hypothermia for cardiac arrest: real-world utilization trends and hospital mortality. J Hosp Med. 2012; 7(9):684-9. PMC: 3515738. DOI: 10.1002/jhm.1974. View

Liu X, Wang M, Chen H, Guo Y, Ma F, Shi F . Hypothermia protects the brain from transient global ischemia/reperfusion by attenuating endoplasmic reticulum response-induced apoptosis through CHOP. PLoS One. 2013; 8(1):e53431. PMC: 3536702. DOI: 10.1371/journal.pone.0053431. View

Deng M, He W, Tan Y, Han H, Hu X, Xia K . Increased expression of reticulon 3 in neurons leads to reduced axonal transport of β site amyloid precursor protein-cleaving enzyme 1. J Biol Chem. 2013; 288(42):30236-30245. PMC: 3798490. DOI: 10.1074/jbc.M113.480079. View

Knight J, Bastide A, Roobol A, Roobol J, Jackson T, Utami W . Eukaryotic elongation factor 2 kinase regulates the cold stress response by slowing translation elongation. Biochem J. 2014; 465(2):227-38. DOI: 10.1042/BJ20141014. View

10.

Richter J, Coller J . Pausing on Polyribosomes: Make Way for Elongation in Translational Control. Cell. 2015; 163(2):292-300. PMC: 4600128. DOI: 10.1016/j.cell.2015.09.041. View

11.

Somers J, Wilson L, Kilday J, Horvilleur E, Cannell I, Poyry T . A common polymorphism in the 5' UTR of ERCC5 creates an upstream ORF that confers resistance to platinum-based chemotherapy. Genes Dev. 2015; 29(18):1891-6. PMC: 4579346. DOI: 10.1101/gad.261867.115. View

12.

Roobol A, Roobol J, Bastide A, Knight J, Willis A, Smales C . p58IPK is an inhibitor of the eIF2α kinase GCN2 and its localization and expression underpin protein synthesis and ER processing capacity. Biochem J. 2014; 465(2):213-25. DOI: 10.1042/BJ20140852. View

13.

He W, Lu Y, Qahwash I, Hu X, Chang A, Yan R . Reticulon family members modulate BACE1 activity and amyloid-beta peptide generation. Nat Med. 2004; 10(9):959-65. DOI: 10.1038/nm1088. View

14.

Knight J, Bastide A, Peretti D, Roobol A, Roobol J, Mallucci G . Cooling-induced SUMOylation of EXOSC10 down-regulates ribosome biogenesis. RNA. 2016; 22(4):623-35. PMC: 4793216. DOI: 10.1261/rna.054411.115. View

15.

Chu D, von der Haar T . The architecture of eukaryotic translation. Nucleic Acids Res. 2012; 40(20):10098-106. PMC: 3488257. DOI: 10.1093/nar/gks825. View

16.

Zhang J, Kaasik K, Blackburn M, Lee C . Constant darkness is a circadian metabolic signal in mammals. Nature. 2006; 439(7074):340-3. DOI: 10.1038/nature04368. View

17.

Moreno J, Radford H, Peretti D, Steinert J, Verity N, Martin M . Sustained translational repression by eIF2α-P mediates prion neurodegeneration. Nature. 2012; 485(7399):507-11. PMC: 3378208. DOI: 10.1038/nature11058. View

18.

Kumamaru E, Kuo C, Fujimoto T, Kohama K, Zeng L, Taira E . Reticulon3 expression in rat optic and olfactory systems. Neurosci Lett. 2004; 356(1):17-20. DOI: 10.1016/j.neulet.2003.11.009. View

19.

Mallucci G, Ratte S, Asante E, Linehan J, Gowland I, Jefferys J . Post-natal knockout of prion protein alters hippocampal CA1 properties, but does not result in neurodegeneration. EMBO J. 2002; 21(3):202-10. PMC: 125833. DOI: 10.1093/emboj/21.3.202. View

20.

Smart F, Aschrafi A, Atkins A, Owens G, Pilotte J, Cunningham B . Two isoforms of the cold-inducible mRNA-binding protein RBM3 localize to dendrites and promote translation. J Neurochem. 2007; 101(5):1367-79. DOI: 10.1111/j.1471-4159.2007.04521.x. View