Role of HSPB8 in the Proteostasis Network: From Protein Synthesis to Protein Degradation and Beyond

Proper protein folding is crucial for protein stability and function; when folding fails, due to stress or genetic mutations, proteins can become toxic. Cells have evolved a complex protein quality control (PQC) system to protect against the toxicity exerted by aberrantly folded proteins, because these species can accumulate in various cellular compartments perturbing essential cellular activities, ultimately leading to cell and neuron death. The PQC comprises molecular chaperones, degradative systems (proteasome and autophagy) and components of the unfolded protein response. Prevention of protein aggregation, clearance of misfolded substrates and attenuation of translation, which decreases the amount of misfolding clients to levels manageable by the molecular chaperones, are all key steps for the maintenance of proteostasis and cell survival. In parallel, alteration of proteostasis may also (indirectly) influence RNA homeostasis; in fact, RNA-containing aggregates, known as stress granules, accumulate in cells with impaired PQC and autophagy and colocalize with proteinaceous aggregates in several neurodegenerative diseases. Among the different molecular chaperones, here we will focus on the small heat shock protein HSPB8, which is expressed in neurons in basal conditions and upregulated in response to misfolded protein accumulation. HSPB8 exerts protective functions in several models of protein conformation neurodegenerative diseases. The putative sites of action of HSPB8 that confer HSPB8 pro-survival and anti aggregation functions are discussed, as well as its potential role at the cross-road between proteostasis and ribostasis.