The Regulation of the Small Heat Shock Protein B8 in Misfolding Protein Diseases Causing Motoneuronal and Muscle Cell Death

Abstract

Misfolding protein diseases are a wide class of disorders in which the aberrantly folded protein aggregates accumulate in affected cells. In the brain and in the skeletal muscle, misfolded protein accumulation induces a variety of cell dysfunctions that frequently lead to cell death. In motoneuron diseases (MNDs), misfolded proteins accumulate primarily in motoneurons, glial cells and/or skeletal muscle cells, altering motor function. The deleterious effects of misfolded proteins can be counteracted by the activity of the protein quality control (PQC) system, composed of chaperone proteins and degradative systems. Here, we focus on a PQC system component: heat shock protein family B (small) member 8 (HSPB8), a chaperone induced by harmful stressful events, including proteotoxicity. In motoneuron and muscle cells, misfolded proteins activate HSPB8 transcription and enhance HSPB8 levels, which contributes to prevent aggregate formation and their harmful effects. HSPB8 acts not only as a chaperone, but also facilitates the autophagy process, to enable the efficient clearance of the misfolded proteins. HSPB8 acts as a dimer bound to the HSP70 co-chaperone BAG3, a scaffold protein that is also capable of binding to HSP70 (associated with the E3-ligase CHIP) and dynein. When this complex is formed, it is transported by dynein to the microtubule organization center (MTOC), where aggresomes are formed. Here, misfolded proteins are engulfed into nascent autophagosomes to be degraded via the chaperone-assisted selective autophagy (CASA). When CASA is insufficient or impaired, HSP70 and CHIP associate with an alternative co-chaperone, BAG1, which routes misfolded proteins to the proteasome for degradation. The finely tuned equilibrium between proteasome and CASA activity is thought to be crucial for maintaining the functional cell homeostasis during proteotoxic stresses, which in turn is essential for cell survival. This fine equilibrium seems to be altered in MNDs, like Amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA), contributing to the onset and the progression of disease. Here, we will review how misfolded proteins may affect the PQC system and how the proper activity of this system can be restored by boosting or regulating HSPB8 activity, with the aim to ameliorate disease progression in these two fatal MNDs.

Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results

“…HSPB8 (Hsp22) shows widespread expression, with the clearly highest levels observed in cardiac and skeletal muscles [394][395][396], and it is induced in proteotoxic stress [397][398][399][400][401][402]. Unlike most other sHSPs, HSPB8 does not seem to form homo-oligomers nor hetero-oligomers with other sHSPs: HSPB8 homodimers form larger oligomers only at high concentrations [189,190], and while interactions of HSPB8 with several other sHSPs have been detected in experimental conditions [20,391,394,403], these are relatively weak [404,405].…”

A Crucial Role for the Protein Quality Control System in Motor Neuron Diseases

“…While “in bulk” autophagy is characterized by a very high clearance capability but is rather non-specific since it entraps large portion of cytoplasm, selective autophagy is highly specific and involves specific molecular regulators (Kaushik and Cuervo, 2018 ). Selective autophagy includes chaperone-assisted selective autophagy (CASA; Arndt et al, 2010 ; Kettern et al, 2011 ; Sarparanta et al, 2012 ; Ulbricht et al, 2013 , 2015 ; Ghaoui et al, 2016 ; Sandell et al, 2016 ; Cicardi et al, 2019 ; Cristofani et al, 2019 ; Rusmini et al, 2019 ), organelles-specific types of autophagy (mitophagy, lysophagy, ribophagy, granulophagy, etc. ), or processes aimed at removing large protein aggregates (aggrephagy; Nivon et al, 2012 ; Stürner and Behl, 2017 ; Aparicio et al, 2020 ).…”

“…Data collected over the last 30 years suggest that ARpolyQ and several ALS-associated proteins (listed in Table 1 ) may lead to PQC system alterations (Kabashi and Durham, 2006 ; Voisine et al, 2010 ; Rusmini et al, 2016 , 2017 ; Cristofani et al, 2018 , 2019 ). At the same time, the boost of key proteins involved in PQC system regulation is protective in SBMA and ALS (Waza et al, 2006 ; Yu et al, 2011 ; Giorgetti et al, 2015 ; Crippa et al, 2016b ; Rusmini et al, 2016 , 2017 , 2019 , 2020 ; Cristofani et al, 2018 , 2019 ; Mandrioli et al, 2019 ).…”

“…BAG1 associates to HSP70 and CHIP to route misfolded proteins to the UPS, while BAG3, in association with HSPB8, interacts with HSP70/CHIP to route misfolded proteins to autophagy ( Figure 2 ). This allows to select which pathway has to be followed by misfolded proteins to be efficiently cleared from cells; the perturbation of this equilibrium may result in misfolded proteins accumulation (Cristofani et al, 2017 , 2019 ; Rusmini et al, 2017 ). The importance of the CASA complex in cell protection against proteotoxicity is underlined by the fact that mutations in the genes coding for almost all components of the CASA complex have been associated with human diseases.…”

ACK1–AR and AR–HOXB13 signaling axes: epigenetic regulation of lethal prostate cancers

“…Consistently, HSPB8 gene expression shows significant differences between patients with prostate adenocarcinoma with metastasis to lymph nodes (LN) LN-N1 compared to LN-N0 with no evidence of metastasis (Figure 7D ). Physiologically, autosomal dominant mutations in HSPB8 are associated with myopathy and benign prostatic hyperplasia ( 113 , 114 ). Molecularly, a role of HSPB8 in conjunction with BAG3 in clearing AR polyQ mutant proteins is proposed in a recent study, which, if not cleared, are associated with spinal and bulbar muscular atrophy, an X-linked motoneuron disease ( 115 ).…”