A Ribosomal Perspective on Proteostasis and Aging Kristan K. Steffen, Andrew Dillin  Cell Metabolism  Volume 23, Issue 6, Pages 1004-1012 (June 2016) DOI: 10.1016/j.cmet.2016.05.013 Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 1 Conserved Stress Response Pathways Alter Translation Initiation in Ways that May Influence Longevity (A and B) eIF2α phosphorylation (A) or 4E-BP activation (B) inhibit cap-dependent translation initiation. (C) Stress alters the ratio of translation initiation events at AUG to non-AUG codons. (D) Stress influences the methylation or pseudouridylation (Ψ) of mRNA, leading to altered translation efficiency. (E) Stress allows more frequent translation initiation at non-canonical sites, including uORFs, internal ribosome entry sites (IRESs), or translation-enhancing elements. Cell Metabolism 2016 23, 1004-1012DOI: (10.1016/j.cmet.2016.05.013) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 2 Translational Regulation Post-initiation Under conditions of proteotoxic stress, the normally ribosome-associated Hsp70 (top panel) instead associates with cytosolic misfolded proteins, resulting in ribosome stalling (bottom panel). Under normal conditions (top panel), NAC inhibits non-secretory mitochondrial proteins (blue chain) from being sorted to the ER, to which ER proteins (red chain) are properly directed. When NAC is depleted, SRP targets both mitochondrial and ER proteins to the ER, resulting in ER and mitochondrial stress (bottom panel). During aging or proteotoxic stress, NAC associates with aggregated proteins (gray disordered chain, bottom panel). The translation elongation factor eEF2 is repressed during stress, resulting in disassociation from ribosomes (bottom panel). Cell Metabolism 2016 23, 1004-1012DOI: (10.1016/j.cmet.2016.05.013) Copyright © 2016 Elsevier Inc. Terms and Conditions