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 found 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 observed that depletion of other chaperones and co-chaperones involved in the degradation of ubiquitinated proteins and DRIPs also affect SG dynamics. Consistently, overexpression of specific chaperone/co-chaperones can modulate the levels of SG markers. These findings further reinforce 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 render the cells particularly vulnerable under challenging/disease conditions, thereby participating to disease progression.

Investigating the interplay between the protein quality control system, molecular chaperones and stress granules: from cell stress response to disease / Carra, Serena. - (2015). ((Intervento presentato al convegno EMBO Workshop: Macromolecular assemblies at the crossroads of cell stress and function tenutosi a Jerusalem, Israel nel 31 Maggio-4 Giugno 2015.

Investigating the interplay between the protein quality control system, molecular chaperones and stress granules: from cell stress response to disease

CARRA, Serena
2015

Abstract

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 found 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 observed that depletion of other chaperones and co-chaperones involved in the degradation of ubiquitinated proteins and DRIPs also affect SG dynamics. Consistently, overexpression of specific chaperone/co-chaperones can modulate the levels of SG markers. These findings further reinforce 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 render the cells particularly vulnerable under challenging/disease conditions, thereby participating to disease progression.
EMBO Workshop: Macromolecular assemblies at the crossroads of cell stress and function
Jerusalem, Israel
31 Maggio-4 Giugno 2015
Carra, Serena
Investigating the interplay between the protein quality control system, molecular chaperones and stress granules: from cell stress response to disease / Carra, Serena. - (2015). ((Intervento presentato al convegno EMBO Workshop: Macromolecular assemblies at the crossroads of cell stress and function tenutosi a Jerusalem, Israel nel 31 Maggio-4 Giugno 2015.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/1074577
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