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Cellular Proteostasis Decline in Human Senescence

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Cellular Proteostasis Decline in Human Senescence Cellular proteostasis decline in human senescence Niv Sabatha,1, Flonia Levy-Adama,1, Amal Younisa,1, Kinneret Rozalesa, Anatoly Mellera, Shani Hadara, Sharon Soueid-Baumgartena, and Reut Shalgia,2 aDepartment of Biochemistry, Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, 31096 Haifa, Israel Edited by Lila M. Gierasch, University of Massachusetts Amherst, Amherst, MA, and approved October 20, 2020 (received for review August 28, 2020) Proteostasis collapse, the diminished ability to maintain protein homeo- induction in aging (10–15), as well as impaired DNA binding ac- stasis, has been established as a hallmark of nematode aging. However, tivity of the HSF1 heat shock (HS) transcription factor (15, 16), whether proteostasis collapse occurs in humans has remained unclear. others have reported that aging has little or no effect on stress- Here, we demonstrate that proteostasis decline is intrinsic to human mediated induction of Hsp70 (17, 18). senescence. Using transcriptome-wide characterization of gene expres- While the general notion of proteostasis collapse being a part of sion, splicing, and translation, we found a significant deterioration in the human aging is plausible, especially given the increased prevalence transcriptional activation of the heat shock response in stressed senes- of proteostasis-related diseases with age, whether proteostasis de- cent cells. Furthermore, phosphorylated HSF1 nuclear localization and cline is in fact a characteristic of human aging still remains unclear. distribution were impaired in senescence. Interestingly, alternative splic- Additionally, there is still a debate whether the proteostasis collapse ing regulation was also dampened. Surprisingly, we found a decoupling in nematodes is the consequence of damaged proteins that have between different unfolded protein response (UPR) branches in stressed accumulated throughout the life of the organism, or whether it is a senescent cells. While young cells initiated UPR-related translational and programmed event (2, 6, 9). transcriptional regulatory responses, senescent cells showed enhanced Here, we decided to directly test whether proteostasis decline translational regulation and endoplasmic reticulum (ER) stress sensing; is a part of human cellular aging. Cellular senescence is a hall- however, they were unable to trigger UPR-related transcriptional re- mark of aging; the relationship between cellular senescence and sponses. This was accompanied by diminished ATF6 nuclear localization human aging is well established (19), and aged mammalian tis- in stressed senescent cells. Finally, we found that proteasome function sues accumulate senescent cells (20, 21). We therefore chose to was impaired following heat stress in senescent cells, and did not re- use primary human fibroblast cells, which undergo replicative cover upon return to normal temperature. Together, our data unraveled senescence, in order to test the hypothesis of the human pro- a deterioration in the ability to mount dynamic stress transcriptional teostasis decline. We exposed young and senescent isogenic cell programs upon human senescence with broad implications on proteo- populations to stress and further performed an in-depth char- stasis control and connected proteostasis decline to human aging. acterization of the transcriptome and translatome of these cells in response to HS using RNA sequencing (RNA-seq) and ribo- protein homeostasis | chaperones | UPR | heat shock response | senescence some footprint profiling (Ribo-seq). We found that human se- nescence shows a significant signature of proteostasis decline. In ging is often characterized by the deterioration in the ability an unbiased analysis of our transcriptome data, a group of more Ato properly respond to external cues. Various systems that than 160 genes, including many chaperones, showed impaired are designed to protect the organism against external assaults induction upon HS in senescent compared to young cells. Ad- lose their ability to efficiently mount a full defense when indi- ditionally, the nuclear localization of phosphorylated HSF1, the viduals age (1). Aging is also accompanied by the accumulation of damaged Significance proteins. Damaged misfolded proteins are targets of the Protein Quality Control (PQC) system, consisting of the proteasome deg- radation system, and a network of molecular chaperones, whose role Protein homeostasis (proteostasis), the balance between pro- is to identify misfolded proteins and to either refold them, target tein synthesis, folding, and degradation, is thought to deteri- them to degradation, or sequester the damaged proteins (2). The orate with age, and the prevalence of protein misfolding ’ ’ chaperone network is also highly induced in response to a variety of diseases (e.g., Alzheimer s, Parkinson s, etc.) with human aging proteotoxic stress conditions that lead to an increased load of mis- is increased. However, while in worms this phenomenon has folded proteins and is often able to efficiently maintain protein ho- been well established, in humans, it remained unclear. Here, meostasis in the face of fluctuating environments (3). However, we show that proteostasis is declined in human cellular aging, damaged proteins, which are often efficiently dealt with and cleared termed cellular senescence. We found that while stress sensing is enhanced in senescent cells, and their response at the level of in young cells, tend to accumulate with age (4). Accordingly, human protein synthesis is intact, they fail to properly activate multi- diseases of protein misfolding and aggregation, such as Alzheimer’s ple programs required for stress adaptation at the level of gene and Parkinson’s disease, are often considered age related, and their transcription. Our findings support the notion that proteostasis prevalence increases dramatically with age (1). decline may have major implications on human aging. Proteostasis collapse has been found and characterized as a hallmark of aging in nematodes (5, 6). Studies have shown that Author contributions: R.S. designed research; F.L.-A., A.Y., K.R., and S.S.-B. performed aging in nematodes is accompanied by a decline in the ability of research; N.S., A.M., and S.H. analyzed data; and R.S. wrote the paper with input from the organism to deal with misfolded proteins and mount an ef- all other authors. ficient proteotoxic stress response (5). The proteostasis collapse The authors declare no competing interest. in nematodes occurs at a specific time frame of adulthood and is This article is a PNAS Direct Submission. linked to the reproductive onset (7–9). Furthermore, a specific This open access article is distributed under Creative Commons Attribution-NonCommercial- chromatin state has been associated with the phenomenon (7). NoDerivatives License 4.0 (CC BY-NC-ND). Although proteostasis collapse in adulthood is well established in 1N.S., F.L.-A., and A.Y. contributed equally to this work. nematodes, whether a similar phenomenon occurs in mammalian 2To whom correspondence may be addressed. Email: [email protected]. species is still unclear. Studies in mammalian organisms over the This article contains supporting information online at https://www.pnas.org/lookup/suppl/ years have mainly focused on Hsp70, with mixed conclusions; while doi:10.1073/pnas.2018138117/-/DCSupplemental. several studies have found an impaired stress-mediated Hsp70 First published November 30, 2020. 31902–31913 | PNAS | December 15, 2020 | vol. 117 | no. 50 www.pnas.org/cgi/doi/10.1073/pnas.2018138117 Downloaded by guest on September 23, 2021 activated form of the HS transcription factor, was compromised chaperone families, with HSP70s, HSP60s, and HSP40s all in senescent cells, as was its nuclear distribution. Furthermore, showing a significant proteostasis decline behavior (SI Appendix, alternative splicing regulation, which we found to be prevalent Fig. S3 E–H). These results indicated that the proteostasis decline upon HS in young cells, was highly diminished in senescent cells, phenomenon we characterized in human cells is even broader and further elaborating the scope of the senescent proteostasis de- spans many of the major chaperone families. cline. Subsequently, using Ribo-seq, we revealed that the un- folded protein response (UPR) of the endoplasmic reticulum HSF1 Nuclear Localization and Distribution upon HS Are Impaired in (ER) was activated in young cells; however, the coordination Senescent Cells. The proteostasis decline observed at the level of between different UPR branches, namely, sensing, translation, transcription, which heavily involved chaperones, suggested that and transcription, was highly impaired in senescent cells; while the transcriptional HS response (HSR) is compromised in se- UPR sensing as well as translational responses were enhanced in nescent cells. We therefore turned to examine the master regu- senescence, senescent cells were unable to initiate UPR-related lator of the HSR, namely, the HSF1 transcription factor. The transcriptional responses. Finally, we showed that the protea- overall mRNA levels of HSF1 were not different in young versus some function is diminished in HS senescent cells and could not senescent cells (SI Appendix, Fig. S4A), and the protein levels recover upon the return of cells to normal growth temperature. were also largely the same (Fig. 3A and SI Appendix, Fig. S4 B These results further illuminate the broad molecular scope of the and C). HSF1 is known to reside in the cytoplasm
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