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.
Attenzione! Scheda prodotto non ancora validata dall'Ateneo
Dati e metadati della pubblicazione sono in fase di verifica da parte dell'Ateneo. In caso di errori o violazione dei diritti d'autore, contattare: email@example.com
|Data di pubblicazione:||2015|
|Titolo:||Investigating the interplay between the protein quality control system, molecular chaperones and stress granules: from cell stress response to disease|
|Data del convegno:||31 Maggio-4 Giugno 2015|
|Nome del convegno:||EMBO Workshop: Macromolecular assemblies at the crossroads of cell stress and function|
|Luogo del convegno:||Jerusalem, Israel|
|Titolo del libro:||EMBO Workshop: Macromolecular assemblies at the crossroads of cell stress and function|
|Appare nelle tipologie:||Relazione in Atti di Convegno|
File in questo prodotto:
I documenti presenti in Iris Unimore sono rilasciati con licenza Creative Commons Attribuzione - Non commerciale - Non opere derivate 3.0 Italia, salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris