title: Dissecting the molecular mechanisms that impair stress granule formation in aging cells.
abstract: Aging affects numerous aspects of cell biology, but the senescence-associated changes in the stress response are only beginning to emerge. To obtain mechanistic insights into these events, we examined the formation of canonical and non-canonical stress granules (SGs) in the cytoplasm. SG generation is a key event after exposure to physiological or environmental stressors. It requires the SG-nucleating proteins G3BP1 and TIA-1/TIAR and stress-related signaling events. To analyze SG formation, we used two independent models of somatic cell aging. In both model systems, cellular senescence impaired the assembly of two SG classes: (i) it compromised the formation of canonical SGs, and (ii) skewed the production of non-canonical SGs. We dissected the mechanisms underlying these senescence-dependent changes in granule biogenesis and identified several specific targets that were modulated by aging. Thus, we demonstrate a depletion of G3BP1 and TIA-1/TIAR in senescent cells and show that the loss of G3BP1 contributed to impaired SG formation. We further reveal that aging reduced Sp1 levels; this transcription factor regulated G3BP1 and TIA-1/TIAR abundance. The assembly of canonical SGs relies on the phosphorylation of translation initiation factor eIF2α. We show that senescence can cause eIF2α hyperphosphorylation. CReP is a subunit of protein phosphatase 1 and critical to reverse the stress-dependent phosphorylation of eIF2α. We demonstrate that the loss of CReP correlated with the aging-related hyperphosphorylation of eIF2α. Together, we have identified significant changes in the stress response of aging cells and provide mechanistic insights. Based on our work, we propose that the decline in SG formation can provide a new biomarker to evaluate cellular aging.
authors.affiliation: Department of Physiology, McGill University, Montreal, Canada.
authors.forename: Ossama
authors.initials: O
authors.lastname: Moujaber
authors.affiliation: Department of Physiology, McGill University, Montreal, Canada.
authors.forename: Hicham
authors.initials: H
authors.lastname: Mahboubi
authors.affiliation: Department of Physiology, McGill University, Montreal, Canada.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Kodiha
authors.affiliation: Department of Physiology, McGill University, Montreal, Canada.
authors.forename: Manuella
authors.initials: M
authors.lastname: Bouttier
authors.affiliation: Department of Physiology, McGill University, Montreal, Canada.
authors.forename: Klaudia
authors.initials: K
authors.lastname: Bednarz
authors.affiliation: Department of Physiology, McGill University, Montreal, Canada.
authors.forename: Ragini
authors.initials: R
authors.lastname: Bakshi
authors.affiliation: Department of Physiology, McGill University, Montreal, Canada.
authors.forename: John
authors.initials: J
authors.lastname: White
authors.affiliation: Department of Medicine, McGill University, Montreal, Canada.
authors.forename: Louise
authors.initials: L
authors.lastname: Larose
authors.affiliation: Department of Rheumatology, McGill University, Montreal, Canada.
authors.forename: Inés
authors.initials: I
authors.lastname: Colmegna
authors.affiliation: Department of Physiology, McGill University, Montreal, Canada. Electronic address: ursula.stochaj@mcgill.ca.
authors.forename: Ursula
authors.initials: U
authors.lastname: Stochaj
mesh_terms: D000818:Animals; D002460:Cell Line; D016922:Cellular Senescence; D003594:Cytoplasmic Granules / Q000378:metabolism* / Q000648:ultrastructure; D004722:Endoribonucleases / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000648:ultrastructure; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D039102:Poly(A)-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013552:Swine
chemical_list: D015852:Eukaryotic Initiation Factor-2; D039102:Poly(A)-Binding Proteins; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D016329:Sp1 Transcription Factor; D004722:Endoribonucleases; D054645:Protein Phosphatase 1
keywords: Aging; Signaling; Sp1; Stress; Stress granules; eIF2α