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.
Highlights
HSPB1 (Hsp27) is a member of the small heat shock protein family, comprising ubiquitously expressed molecular chaperones whose canonical function is to preserve cellular proteostasis during stress conditions
Given the increased interaction of poly(C)binding protein 1 (PCBP1) with the HSPB1-P182L mutant, we evaluated the effect of the P182L mutation on PCBP1 cellular localization, which is mostly present in the nucleus and noticeable expressed in the cytosol
Besides the clear presence of neuronal transcripts seen among the mRNA targets containing PCBP1 recognition motifs, we identified known genes associated with hereditary peripheral neuropathies and hereditary spastic paraplegias
Summary
HSPB1 (Hsp27) is a member of the small heat shock protein family (sHSPs), comprising ubiquitously expressed molecular chaperones whose canonical function is to preserve cellular proteostasis during stress conditions. In contrast to heat shock proteins with an ATPase domain (e.g., HSP70), sHSPs do not have the intrinsic capacity to refold denatured proteins. They are able to bind to unfolded proteins keeping them in a folding-competent state. The CMT2F patients typically present with mixed sensory and motor symptoms, while motor neurons are predominantly affected in patients with dHMN type II [24]. It is surprising that mutations in this ubiquitously expressed molecular chaperone affect the peripheral nerves suggesting a key role in the highly polarized motor and sensory neurons
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