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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0407-3) contains supplementary material, which is available to authorized users.

Unbiased detection of CRISPR off-targets in vivo using DISCOVER-Seq

“…The patient carries a heterozygous missense mutation (P182L) in heat-shock protein B1 (HSPB1) resulting in a dominant negative neuropathic phenotype with a loss of motor neuron function ( 40 ). Mice heterozygous for HSPB1 show no disease phenotype, so an attractive therapeutic strategy is to knock out the disease allele without affecting the intact copy of HSPB1 , ( 41 , 42 ). For this strategy to move into the clinic, it is important to characterize potential missense-targeting editing reagents in detail, ideally in a patient-specific manner.…”

Small heat shock proteins in neurodegenerative diseases

“…Besides its canonical chaperone function, HSPB1 is involved in numerous cellular processes, such as apoptosis (Charette et al 2000;Qi et al 2014), cytoskeleton dynamics (Der Perng and Quinlan 2004;Almeida-Souza et al 2011;Clarke and Mearow 2013), translation (Cuesta et al 2000;Geuens et al 2017), and autophagy (Tang et al 2011;Matsumoto et al 2015). Haidar et al (2019) recently showed that different mutations in HSPB1 (R127W, S135F, and P182L) lead to an impairment of autophagy, a ubiquitous multi-step process which prevents the accumulation of misfolded proteins and damaged organelles in the cytoplasm.…”

Expanded polyglutamine impairs normal nuclear distribution of fused in sarcoma and poly (rC)‐binding protein 1 in Huntington's disease

“…There are limited reports of a role of PCBP1 in neurodegenerative diseases. For example, PCBP1 was reported to interact with the HSPB1‐P182L mutant, as well as other genes causing hereditary neurological disorders . However, to our knowledge there are no reports suggesting a role of PCBP1 in HD.…”