Interrelation between protein synthesis, proteostasis and life span

Abstract

The production of newly synthesized proteins is a key process of protein homeostasis that initiates the biosynthetic flux of proteins and thereby determines the composition, stability and functionality of the proteome. Protein synthesis is highly regulated on multiple levels to adapt the proteome to environmental and physiological challenges such as aging and proteotoxic conditions. Imbalances of protein folding conditions are sensed by the cell that then trigger a cascade of signaling pathways aiming to restore the protein folding equilibrium. One regulatory node to rebalance proteostasis upon stress is the control of protein synthesis itself. Translation is reduced as an immediate response to perturbations of the protein folding equilibrium that can be observed in the cytosol as well as in the organelles such as the endoplasmatic reticulum and mitochondria. As reduction of protein synthesis is linked to life span increase, the signaling pathways regu-lating protein synthesis might be putative targets for treatments of age-related diseases. Eukaryotic cells have evolved a complex system for protein synthesis regulation and this review will summarize cellular strategies to regulate mRNA translation upon stress and its impact on longevity.

Keywords: Aging; Chaperone; Life span; Proteostasis; Stress response; UPR.; mRNA Translation.

Fig. (1)

Protein synthesis regulation in stress – an overview. (A) Upon stress (e.g. dietary restriction, heat shock) global protein synthesis is reduced by a complex cross-compartmental network of stress response pathways (TOR, GCN-2, PERK), which interact with components of the eIF4F complex (eIF4A, eIF4E, eIF4G) and 43S (40S, eIF1, eIF1A, eIF2, eIF3, eIF5) and thereby disturb mRNA translation initiation [15]. Dotted lines indicate general pathway interconnections which can be activating and/or inhibiting. Chaperones also regulate mRNA translation either by ribosome dissociation, which causes ribosomal stalling (NAC, Hsp70) or by interaction with PABP/eIF4G (Hsp27). (B) Enhanced synthesis of stress response proteins, e.g. chaperones, degradation machineries, transcriptions factors (TF), is mediated by IRES, uORFs and TOP elements, enabling protein synthesis in conditions where global mRNA translation is reduced. Cytosolic, mitochondrial and ER stress responses recruit TFs (e.g. HSF-1, ATFS-1, XBP-1) to induce compartment-specific stress response protein production.

Fig. (2)

Tissue-specific and tissue-spanning stress responses in C. elegans. (A) Stress responses, e.g. UPR^ER, in neurons can generate signals that are transmitted to distal intestinal cells to induce similar stress responses there. This cell non-autonomous signaling could be achieved by exchange of small molecules (e.g. peptides, neurotransmitter, regulatory RNA) [96, 98]. (B) Trans-cellular-chaperone signaling (TCCS) allows cross-tissue Hsp90 adaptation, which causes also reduced HSR in distal tissues due to HSF-1 inactivation by Hsp90. PHA-4 (orthologue of FoxA) -mediated trans-cellular-signaling allows HSR activation upon Hsp90 knockdown. (C) Attenuation of global mRNA translation is caused by reduction of ILS signaling/dietary restriction and expression of proteotoxic proteins, e.g. Aβ and polyQ proteins. Upon ILS signaling reduction the expression of muscle components is maintained to allow locomotion upon starvation. (D) Knockdown of HSR negative regulators (HNR 1 to 3) causes induction of tissue-specific Hsp70 expression (filled squares) in intestine (I), muscles (II) and spermatheca (III).