Impairment of the Protein Quality Control System Affects Stress Granule Response and Dynamics

Stress granules (SGs) are transient heterogeneous mRNA-protein complexes induced during stress. SGs exert cellular pro-survival functions and recent data suggest deregulation of SG response and dynamics as potential pathomechanism in e.g. amyotrophic lateral sclerosis, frontotemporal lobar degeneration and multisystem proteinopathy. These diseases can be associated with mutations of valosin-containing protein (VCP) and are characterized by impairment of the protein quality control (PQC), as well as aggregation of SG components. 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. Thus, due to the crowded molecular environment, SGs may, indirectly, require protein quality control (PQC) assistance for proper assembly and disassembly. Here we investigated whether impairment of PQC, autophagy and lysosome-mediated degradation may affect SG response. We demonstrated 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 found that 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 observed that depletion of other chaperones and co-chaperones involved in the degradation of ubiquitinated proteins and DRIPs also affects SG dynamics. This further reinforces the hypothesis that PQC and SGs are tightly interconnected. Collectively our data suggest that besides causing a protein homeostasis imbalance, deregulated autophagy, lysosomal or chaperone activities may also alter SG morphology, composition and dynamics. This, in turn, may lead to defective SG disassembly and persistence, thereby ultimately increasing cell vulnerability, especially under challenging/disease conditions.