Characterization of the interplay between the protein quality control and the stress granule response: implication in neurodegenerative diseases

Stress granules (SGs) are transient heterogeneous mRNA-protein complexes induced during stress, which exert cellular pro-survival functions. Recent data implicate SGs and deregulated proteostasis in amyotrophic lateral sclerosis, frontotemporal lobar degeneration and multisystem proteinopathy, which are also associated with mutations of valosin-containing protein (VCP) and where protein aggregates that contain components of SGs accumulate. This suggests that inappropriate SG dynamics may be relevant to pathogenesis. Interestingly, SG formation is driven by the reversible self-aggregation of mRNA-binding proteins that contain prion-like domains. Unlike prionogenic fibrillar aggregates, SGs are dynamic structures, which disassemble within few hours after their formation, even if the stress persists. Due to the heterogeneous composition of SGs and to the crowded molecular environment, SGs may, indirectly, require protein quality control (PQC) assistance for proper assembly and disassembly. Previously, the autophagy-lysosome pathway and VCP, key players of the PQC, were shown to regulate SG degradation (Buchan et al., Cell 2013). Here we investigated whether impairment of PQC, autophagy and lysosome-mediated degradation may affect SG response. We provide evidence supporting that inhibition of VCP, autophagy or lysosomes affects SG formation, morphology and composition. In particular, defective ribosomal products (DRIPs) and the large ribosome subunit 60S, which are released from disassembling polysomes, are normally excluded from SGs. Instead, we observed that both DRIPs and 60S were significantly retained within and/or adjacent to SGs in cells with impaired autophagy, lysosome, or VCP function (Seguin et al., CDD 2014). Next, we found that depletion of other chaperones and co-chaperones involved in the degradation of ubiquitinated proteins and DRIPs also affect SG dynamics and translation restoration after stress. These findings further reinforce the hypothesis that PQC and SGs are tightly interconnected and work in concert to maintain and restore protein and RNA homeostasis. Deregulation of the PQC would thus render the cells particularly vulnerable under challenging/disease conditions, thereby participating to disease progression.