Inhibition of autophagy, lysosome and VCP alters stress granule morphology and composition

Stress granules (SGs) are mRNA-protein aggregates induced during stress, which accumulate in many age-related neurodegenerative diseases. Previously, the autophagy-lysosome pathway and valosin-containing protein (VCP), key players of the protein quality control (PQC), were shown to regulate SG degradation (Buchan et al., Cell 2013). This is consistent with the idea that PQC may survey and/or assist SG dynamics. However, despite these observations, it is currently unknown whether the PQC actively participates in SG assembly. Here we investigated whether impairment of PQC, autophagy and lysosome-mediated degradation may affect SG assembly. We provide evidence supporting that inhibition of VCP, autophagy or lysosomes affects SG formation, morphology and composition. In particular, defective ribosomal products and 60S, which are released from disassembling polysomes and are normally excluded from SGs, were significantly retained within SGs in cells with impaired autophagy, lysosome, or VCP function. Recent data implicate SGs and deregulated proteostasis in amyotrophic lateral sclerosis, frontotemporal lobar degeneration and multisystem proteinopathy, which, intriguingly, are also associated with VCP mutations and where protein aggregates that contain components of SGs accumulate. This suggests that inappropriate SG dynamics may be relevant to pathogenesis. Our data are in line with such a hypothesis and suggest that deregulated autophagy, lysosomal or VCP activities may alter SG morphology and composition. This, in turn, may render the cells particularly vulnerable under challenging/disease conditions, thereby participating to disease progression.