Date Published: June 14, 2017
Publisher: John Wiley and Sons Inc.
Author(s): Matea Perić, Anita Lovrić, Ana Šarić, Marina Musa, Peter Bou Dib, Marina Rudan, Andrea Nikolić, Sandra Sobočanec, Ana‐Matea Mikecin, Sven Dennerlein, Ira Milošević, Kristian Vlahoviček, Nuno Raimundo, Anita Kriško.
Protein quality control mechanisms, required for normal cellular functioning, encompass multiple functions related to protein production and maintenance. However, the existence of communication between proteostasis and metabolic networks and its underlying mechanisms remain elusive. Here, we report that enhanced chaperone activity and consequent improved proteostasis are sensed by TORC1 via the activity of Hsp82. Chaperone enrichment decreases the level of Hsp82, which deactivates TORC1 and leads to activation of Snf1/AMPK, regardless of glucose availability. This mechanism culminates in the extension of yeast replicative lifespan (RLS) that is fully reliant on both TORC1 deactivation and Snf1/AMPK activation. Specifically, we identify oxygen consumption increase as the downstream effect of Snf1 activation responsible for the entire RLS extension. Our results set a novel paradigm for the role of proteostasis in aging: modulation of the misfolded protein level can affect cellular metabolic features as well as mitochondrial activity and consequently modify lifespan. The described mechanism is expected to open new avenues for research of aging and age‐related diseases.
Protein homeostasis (proteostasis) encompasses the equilibrium between synthesis, conformational maintenance, and degradation of damaged proteins. While protein synthesis has a critical role in making the proteome and promoting cell growth, failure to eliminate misfolded proteins can lead to inactivation of functional proteins as well as cell degeneration and death. Cellular proteostasis is maintained by a network of molecular chaperones, protein degradation machineries, and stress–response pathways, whose coordinated action senses and counteracts protein misfolding (Wolff et al., 2014). Molecular chaperones, including the heat‐shock proteins (HSPs), are ubiquitously present cellular proteins, which display a wide spectrum of folding‐oriented activities, coping with regular protein folding events, as well as stress‐induced protein misfolding (Morano et al., 1998). The efficiency of proteostasis may decline, with well‐described consequences, especially in the context of numerous diseases and aging (Labbadia & Morimoto, 2015). As a result of such a decline, proteins cannot maintain their native fold or perform their function and, consequently, cells promote the removal of damaged proteins through their degradation, refolding, and/or aggregation (Brandvold & Morimoto, 2015). On the other hand, the research on phenotypes related to the alleviation of protein misfolding is not keeping pace. The improvement of disaggregase activity in yeast was found to diminish the accumulation of insoluble aggregates during aging and restored degradation of 26S proteasome substrates in aged cells (Andersson et al., 2013). Because of extensive interest, the cell‐wide response to the enrichment in chaperone activity has not received any attention.
The relationship between cellular proteostasis and the metabolic processes can be considered a central homeostatic mechanism, and its importance is unequivocal. Yet, almost nothing is known about this connection and its role in cellular functioning. More specifically, it is vague which pathway performs the sensing of the folding environment, as well as if and how such information is relayed to other cellular networks. Furthermore, while it is rather well described how a cell responds to proteotoxic stress in the context of stress responses, nothing is known about cellular response to alleviation of protein misfolding.
This work was supported by the Fondation Nelia et Amedeo Barletta, NAOS Group, and the Mediterranean Institute for Life Sciences to AV, MP, MM, MR, AN, and AK; Croatian Ministry of Science, Education and Sports, Grant No. 098‐0982464‐1647 to AŠ and SS; European Commission Seventh Framework Program, Integra‐Life; grant 315997 to KV; FP7‐REGPOT‐2012‐2013‐1, Grant No. 316289, InnoMol to AMM; grant 337327 from the European Research Council to NR and PBD; IM is supported by an Emmy Noether Award from the Deutsche Forschungsgemeinschaft.
The study was designed by NR and AK; data were generated and analyzed by MP, AL, AŠ, SS, MR, MM, AN, PBD, AMM, SD, NR, and AK; consultation on spinning disk imaging was provided by IM; RNA sequencing data analysis was designed and conducted by KV; the manuscript was written by NR, KV, and AK.
The authors have no conflict of interest to declare.