Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Volume 1864, Issue 3, Pages 475-486Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamcr.2016.12.008
Keywords
Aging; Stress; Stress granules; Signaling; elF2 alpha; Sp1
Categories
Funding
- Fonds quebecois de la recherche sur la nature et les technologies (FRQNT)
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- Alexander Graham Bell Canada Graduate Scholarship from NSERC
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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/FIAR 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/FIAR abundance. The assembly of canonical SGs relies on the phosphorylation of translation initiation factor elF2 alpha. We show that senescence can cause elF2 alpha hyperphosphorylation. CReP is a subunit of protein phosphatase 1 and critical to reverse the stress-dependent phosphorylation of elF2a. We demonstrate that the loss of CReP correlated with the aging-related hyperphosphorylation of elF2 alpha. 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. (C) 2016 Elsevier B.V. All rights reserved.
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