title: Mutant HSPB1 causes loss of translational repression by binding to PCBP1, an RNA binding protein with a possible role in neurodegenerative disease.
abstract: The small heat shock protein HSPB1 (Hsp27) is an ubiquitously expressed molecular chaperone able to regulate various cellular functions like actin dynamics, oxidative stress regulation and anti-apoptosis. So far disease causing mutations in HSPB1 have been associated with neurodegenerative diseases such as distal hereditary motor neuropathy, Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis. Most mutations in HSPB1 target its highly conserved α-crystallin domain, while other mutations affect the C- or N-terminal regions or its promotor. Mutations inside the α-crystallin domain have been shown to enhance the chaperone activity of HSPB1 and increase the binding to client proteins. However, the HSPB1-P182L mutation, located outside and downstream of the α-crystallin domain, behaves differently. This specific HSPB1 mutation results in a severe neuropathy phenotype affecting exclusively the motor neurons of the peripheral nervous system. We identified that the HSPB1-P182L mutant protein has a specifically increased interaction with the RNA binding protein poly(C)binding protein 1 (PCBP1) and results in a reduction of its translational repressive activity. RNA immunoprecipitation followed by RNA sequencing on mouse brain lead to the identification of PCBP1 mRNA targets. These targets contain larger 3'- and 5'-UTRs than average and are enriched in an RNA motif consisting of the CTCCTCCTCCTCC consensus sequence. Interestingly, next to the clear presence of neuronal transcripts among the identified PCBP1 targets we identified known genes associated with hereditary peripheral neuropathies and hereditary spastic paraplegias. We therefore conclude that HSPB1 can mediate translational repression through interaction with an RNA binding protein further supporting its role in neurodegenerative disease.
authors.affiliation: Peripheral Neuropathy Group, Department of Molecular Genetics, VIB, Institute Born Bunge and University of Antwerp, Antwerpen, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Geuens
authors.affiliation: Peripheral Neuropathy Group, Department of Molecular Genetics, VIB, Institute Born Bunge and University of Antwerp, Antwerpen, Belgium.
authors.forename: Vicky
authors.initials: V
authors.lastname: De Winter
authors.affiliation: Center for Human Genetics, Center for the Biology of Disease, VIB and KU Leuven, Leuven, Belgium.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Rajan
authors.affiliation: Center for Human Genetics, Center for the Biology of Disease, VIB and KU Leuven, Leuven, Belgium.|Department of Fundamental Neuroscience (DNF), University of Lausanne, Lausanne, Switzerland.
authors.forename: Tilmann
authors.initials: T
authors.lastname: Achsel
authors.affiliation: Department of Molecular Genetics, VIB and University of Antwerp, Antwerpen, Belgium.
authors.forename: Ligia
authors.initials: L
authors.lastname: Mateiu
authors.affiliation: Peripheral Neuropathy Group, Department of Molecular Genetics, VIB, Institute Born Bunge and University of Antwerp, Antwerpen, Belgium.|Present address: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Almeida-Souza
authors.affiliation: Department of Molecular Genetics, VIB and University of Antwerp, Antwerpen, Belgium.
authors.forename: Bob
authors.initials: B
authors.lastname: Asselbergh
authors.affiliation: Peripheral Neuropathy Group, Department of Molecular Genetics, VIB, Institute Born Bunge and University of Antwerp, Antwerpen, Belgium.
authors.forename: Delphine
authors.initials: D
authors.lastname: Bouhy
authors.affiliation: Institute of Medical Biology and Department of Internal Medicine, Diabetes and Metabolism, Medical University Graz, Graz, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Auer-Grumbach
authors.affiliation: Center for Human Genetics, Center for the Biology of Disease, VIB and KU Leuven, Leuven, Belgium.|Department of Fundamental Neuroscience (DNF), University of Lausanne, Lausanne, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bagni
authors.affiliation: Peripheral Neuropathy Group, Department of Molecular Genetics, VIB, Institute Born Bunge and University of Antwerp, Antwerpen, Belgium. vincent.timmerman@molgen.vib-ua.be.
authors.forename: Vincent
authors.initials: V
authors.lastname: Timmerman
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism; D016384:Consensus Sequence; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D057809:HEK293 Cells; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018832:Molecular Chaperones; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D014176:Protein Biosynthesis / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins; D020506:Untranslated Regions
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D034441:Heterogeneous-Nuclear Ribonucleoproteins; C486113:Hsbp1 protein, mouse; D018832:Molecular Chaperones; D050505:Mutant Proteins; D009363:Neoplasm Proteins; C094604:PCBP1 protein, human; C121375:Pcbp1 protein, mouse; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D020506:Untranslated Regions
keywords: Charcot-Marie-Tooth; Distal Hereditary Motor Neuropathy; HSPB1; PCBP1; RNA immunoprecipitation