The Role of the Heat Shock Protein B8 (HSPB8) in Motoneuron Diseases

Abstract

Amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA) are two motoneuron diseases (MNDs) characterized by aberrant protein behavior in affected cells. In familial ALS (fALS) and in SBMA specific gene mutations lead to the production of neurotoxic proteins or peptides prone to misfold, which then accumulate in form of aggregates. Notably, some of these proteins accumulate into aggregates also in sporadic ALS (sALS) even if not mutated. To prevent proteotoxic stresses detrimental to cells, misfolded and/or aggregated proteins must be rapidly removed by the protein quality control (PQC) system. The small heat shock protein B8 (HSPB8) is a chaperone induced by harmful events, like proteasome inhibition. HSPB8 is expressed both in motoneuron and muscle cells, which are both targets of misfolded protein toxicity in MNDs. In ALS mice models, in presence of the mutant proteins, HSPB8 is upregulated both in spinal cord and muscle. HSPB8 interacts with the HSP70 co-chaperone BAG3 and enhances the degradation of misfolded proteins linked to sALS, or causative of fALS and of SBMA. HSPB8 acts by facilitating autophagy, thereby preventing misfolded protein accumulation in affected cells. BAG3 and BAG1 compete for HSP70-bound clients and target them for disposal to the autophagy or proteasome, respectively. Enhancing the selective targeting of misfolded proteins by HSPB8-BAG3-HSP70 to autophagy may also decrease their delivery to the proteasome by the BAG1-HSP70 complex, thereby limiting possible proteasome overwhelming. Thus, approaches aimed at potentiating HSPB8-BAG3 may contribute to the maintenance of proteostasis and may delay MNDs progression.

Keywords: HSPB8; amyotrophic lateral sclerosis; autophagy; chaperones; misfolded proteins; motoneuron diseases; proteasome; spinal and bulbar muscular atrophy.

Figure 1

Proteostasis in neurodegenerative disorders. Molecular chaperones assist proteins to acquire the proper folding. When folding fails, the chaperones allow the ubiquitination and route misfolded proteins to degradative systems. This process is mediated by the HSC70-CHIP complex that interacts with nucleotide exchange factor (NEF)/BCL2-associated athanogenes (BAGs; HSC70 co-chaperones). BAG1 routes misfolded proteins to ubiquitin proteasome system (UPS). Alternatively, BAG3 and specific chaperone heat shock protein B8 (HSPB8; B8 in the figure) promote the degradation of HSC70 substrates via autophagy. The HSC70-CHIP interaction with BAG1 inhibits the HSP70 chaperone activity and allows misfolded proteins polyubiquitination by HSC70-binding co-factor CHIP resulting in misfolded proteins degradation via UPS. BAG3 interacts with dynein and 14-3-3 protein moving misfolded proteins to microtubule organization center (MTOC) where aggresomes are assembled. Polyubiquitinated proteins linked to HSC70-BAG3 are recognized by SQSTM1/p62 and its interaction with LC3 allows misfolded proteins insertion into autophagosomes.

Figure 2

Regulation of protein quality control (PQC) system. When misfolded proteins cannot be efficiently removed by degradative pathways, misfolded proteins may accumulate and block ubiquitin proteasome system (UPS) and autophagy. In this context, proteasome saturation by misfolded proteins increases the transcription of HSPB8 (B8 in the figure) that, together with its partners BAG3 and HSC70, routes misfolded proteins to autophagy. In parallel, when dynein-mediated transport is blocked and autophagosomes formation is inhibited, still unknown factors activate the de novo transcription of BAG1, which binds to HSP70/CHIP and routes misfolded proteins to UPS.