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Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Geuens, T; De Winter, V; Rajan, N; Achsel, T; Mateiu, L; Almeida-Souza, L; Asselbergh, B; Bouhy, D; Auer-Grumbach, M; Bagni, C; Timmerman, V.
Mutant HSPB1 causes loss of translational repression by binding to PCBP1, an RNA binding protein with a possible role in neurodegenerative disease.
Acta Neuropathol Commun. 2017; 5(1):5-5
Doi: 10.1186/s40478-016-0407-3
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- Co-authors Med Uni Graz
- Auer-Grumbach Michaela
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Brain - metabolism
- Carrier Proteins - genetics
- Carrier Proteins - metabolism
- Charcot-Marie-Tooth Disease - genetics
- Charcot-Marie-Tooth Disease - metabolism
- Consensus Sequence -
- Fibroblasts - metabolism
- Gene Expression Regulation - physiology
- HEK293 Cells -
- HSP27 Heat-Shock Proteins - genetics
- HSP27 Heat-Shock Proteins - metabolism
- HeLa Cells -
- Heat-Shock Proteins - genetics
- Heat-Shock Proteins - metabolism
- Heterogeneous-Nuclear Ribonucleoproteins - genetics
- Heterogeneous-Nuclear Ribonucleoproteins - metabolism
- Humans -
- Mice -
- Mutant Proteins - genetics
- Mutant Proteins - metabolism
- Mutation -
- Neoplasm Proteins - genetics
- Neoplasm Proteins - metabolism
- Protein Binding -
- Protein Biosynthesis - physiology
- RNA, Messenger - genetics
- RNA, Messenger - metabolism
- Untranslated Regions -
- Find related publications in this database (Keywords)
- HSPB1
- RNA immunoprecipitation
- PCBP1
- Distal Hereditary Motor Neuropathy
- Charcot-Marie-Tooth