The FUS gene is dual-coding with both proteins contributing to FUS-mediated toxicity.
FUS
alternative ORF
amyotrophic lateral sclerosis
dual coding
polycistronic
Journal
EMBO reports
ISSN: 1469-3178
Titre abrégé: EMBO Rep
Pays: England
ID NLM: 100963049
Informations de publication
Date de publication:
07 01 2021
07 01 2021
Historique:
received:
14
04
2020
revised:
08
10
2020
accepted:
13
10
2020
pubmed:
24
11
2020
medline:
1
6
2021
entrez:
23
11
2020
Statut:
ppublish
Résumé
Novel functional coding sequences (altORFs) are camouflaged within annotated ones (CDS) in a different reading frame. We show here that an altORF is nested in the FUS CDS, encoding a conserved 170 amino acid protein, altFUS. AltFUS is endogenously expressed in human tissues, notably in the motor cortex and motor neurons. Over-expression of wild-type FUS and/or amyotrophic lateral sclerosis-linked FUS mutants is known to trigger toxic mechanisms in different models. These include inhibition of autophagy, loss of mitochondrial potential and accumulation of cytoplasmic aggregates. We find that altFUS, not FUS, is responsible for the inhibition of autophagy, and pivotal in mitochondrial potential loss and accumulation of cytoplasmic aggregates. Suppression of altFUS expression in a Drosophila model of FUS-related toxicity protects against neurodegeneration. Some mutations found in ALS patients are overlooked because of their synonymous effect on the FUS protein. Yet, we show they exert a deleterious effect causing missense mutations in the overlapping altFUS protein. These findings demonstrate that FUS is a bicistronic gene and suggests that both proteins, FUS and altFUS, cooperate in toxic mechanisms.
Identifiants
pubmed: 33226175
doi: 10.15252/embr.202050640
pmc: PMC7788448
doi:
Substances chimiques
FUS protein, human
0
RNA-Binding Protein FUS
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e50640Subventions
Organisme : CIHR
ID : MOP-136962
Pays : Canada
Organisme : Medical Research Council
ID : MR/S006591/1
Pays : United Kingdom
Organisme : CIHR
ID : MOP-137056
Pays : Canada
Informations de copyright
© 2020 The Authors. Published under the terms of the CC BY 4.0 license.
Références
Nat Chem Biol. 2015 Dec;11(12):909-16
pubmed: 26575237
Virology. 2019 Jun;532:39-47
pubmed: 31004987
Cell. 2018 Apr 19;173(3):720-734.e15
pubmed: 29677515
Protein Cell. 2011 Mar;2(3):223-36
pubmed: 21452073
Hum Mol Genet. 2013 Dec 1;22(23):4748-55
pubmed: 23847048
Exp Neurol. 2018 Jan;299(Pt A):15-25
pubmed: 28941811
Acta Neuropathol Commun. 2016 Sep 06;4(1):99
pubmed: 27600654
Nat Commun. 2018 May 22;9(1):2010
pubmed: 29789581
PLoS Comput Biol. 2011 Oct;7(10):e1002212
pubmed: 21998575
Biochem Biophys Res Commun. 2017 Feb 19;483(4):1187-1193
pubmed: 27416757
Nat Rev Neurol. 2013 Nov;9(11):617-28
pubmed: 24126629
Mitochondrion. 2016 Jan;26:94-103
pubmed: 26702583
Protein Cell. 2011 Jun;2(6):477-86
pubmed: 21748598
Nat Commun. 2014 Jul 09;5:4335
pubmed: 25004804
Science. 2009 Feb 27;323(5918):1208-1211
pubmed: 19251628
Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5429-34
pubmed: 20212158
Brain Res. 2016 Oct 15;1649(Pt B):189-200
pubmed: 27181519
Sci Rep. 2018 Oct 22;8(1):15575
pubmed: 30349096
Neurobiol Aging. 2012 May;33(5):1008.e1-15
pubmed: 22118902
Cell Rep. 2017 May 30;19(9):1739-1749
pubmed: 28564594
FASEB J. 2011 Jul;25(7):2373-86
pubmed: 21478263
PLoS Biol. 2011 Apr;9(4):e1001052
pubmed: 21541368
PLoS Genet. 2015 Sep 03;11(9):e1005357
pubmed: 26335776
Sci Rep. 2015 Aug 21;5:13416
pubmed: 26293199
Nucleic Acids Res. 2018 Jan 4;46(D1):D823-D830
pubmed: 28977460
Trends Biochem Sci. 2016 Nov;41(11):898-906
pubmed: 27647212
Acta Neuropathol. 2011 Mar;121(3):421-7
pubmed: 20721566
Nucleic Acids Res. 2019 Jan 8;47(D1):D403-D410
pubmed: 30299502
Biochemistry. 2018 Jul 10;57(27):4010-4018
pubmed: 29936833
Acta Neuropathol. 2019 Jul;138(1):67-84
pubmed: 30937520
Elife. 2017 Oct 30;6:
pubmed: 29083303
Mol Cell Proteomics. 2018 Dec;17(12):2402-2411
pubmed: 30181344
Eur J Neurol. 2012 Jul;19(7):977-83
pubmed: 22340366
Genome Res. 2019 Mar;29(3):485-493
pubmed: 30610011
Nat Methods. 2013 Aug;10(8):730-6
pubmed: 23921808
Ann Neurol. 2010 Jun;67(6):739-48
pubmed: 20517935
Genet Med. 2015 May;17(5):405-24
pubmed: 25741868
Elife. 2019 Feb 12;8:
pubmed: 30747709
Behav Brain Res. 2013 Sep 15;253:95-102
pubmed: 23871228
Nat Biotechnol. 2015 Jul;33(7):743-9
pubmed: 26076430
Acta Neuropathol Commun. 2015 Apr 25;3:24
pubmed: 25907258
EMBO J. 2016 May 17;35(10):1077-97
pubmed: 26951610
Nucleic Acids Res. 2018 Jan 4;46(D1):D754-D761
pubmed: 29155950
Brain. 2019 Sep 1;142(9):2572-2580
pubmed: 31368485
Brain. 2019 May 1;142(5):1176-1194
pubmed: 30938443
Acta Neuropathol Commun. 2019 Jan 14;7(1):7
pubmed: 30642400
Proc Natl Acad Sci U S A. 2010 Sep 14;107(37):16325-30
pubmed: 20736350
Nature. 2016 Nov 10;539(7628):197-206
pubmed: 27830784
Cell Rep. 2018 Jul 17;24(3):529-537.e4
pubmed: 30021151
EMBO Mol Med. 2018 Jan;10(1):48-62
pubmed: 29191947
J Proteome Res. 2015 Nov 6;14(11):4486-501
pubmed: 26401960
Front Cell Neurosci. 2015 Oct 23;9:423
pubmed: 26557057
Int J Mol Sci. 2018 Mar 16;19(3):
pubmed: 29547565
Oxid Med Cell Longev. 2017;2017:5716409
pubmed: 28894508
Nat Rev Neurol. 2014 Jun;10(6):337-48
pubmed: 24840975
Acta Neuropathol. 2012 Nov;124(5):733-47
pubmed: 22941224
Nat Commun. 2018 Jan 23;9(1):335
pubmed: 29362359
Hum Mol Genet. 2011 Jul 1;20(13):2510-23
pubmed: 21487023
Sci Rep. 2019 Mar 14;9(1):4572
pubmed: 30872738
Nat Genet. 2000 Feb;24(2):175-9
pubmed: 10655065
Genome Res. 2018 May;28(5):609-624
pubmed: 29626081
Nucleic Acids Res. 2018 Jan 4;46(D1):D497-D502
pubmed: 29140531
Genet Mol Res. 2011 Mar 22;10(1):494-505
pubmed: 21476195
Nat Methods. 2011 Jan;8(1):70-3
pubmed: 21131968
Proteomics. 2018 May;18(10):e1700058
pubmed: 28627015
NPJ Aging Mech Dis. 2019 May 21;5:6
pubmed: 31123597