Protein quality control during aging involves recruitment of the macroautophagy pathway by BAG3
Open accessAbstract
The Hsc/Hsp70 co-chaperones of the BAG (Bcl-2-associated athanogene) protein family are modulators of protein quality control. We examined the specific roles of BAG1 and BAG3 in protein degradation during the aging process. We show that BAG1 and BAG3 regulate proteasomal and macroautophagic pathways, respectively, for the degradation of polyubiquitinated proteins. Moreover, using models of cellular aging, we find that a switch from BAG1 to BAG3 determines that aged cells use more intensively the macroautophagic system for turnover of polyubiquitinated proteins. This increased macroautophagic flux is regulated by BAG3 in concert with the ubiquitin-binding protein p62/SQSTM1. The BAG3/BAG1 ratio is also elevated in neurons during aging of the rodent brain, where, consistent with a higher macroautophagy activity, we find increased levels of the autophagosomal marker LC3-II as well as a higher cathepsin activity. We conclude that the BAG3-mediated recruitment of the macroautophagy pathway is an important adaptation of the protein quality control system to maintain protein homeostasis in the presence of an enhanced pro-oxidant and aggregation-prone milieu characteristic of aging.
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Increasing data indicate a significant association between senescence and autophagy in various cell systems.
“Increasing data indicate a significant association between senescence and autophagy in various cell systems (Gerland et al. 2003; Gamerdinger et al. 2009; Sasaki et al. 2010; Capparelli et al. 2012; Dörr et al. 2013).”
From Cellular senescence and its effector programs (2014) · cites this paper as Gamerdinger et al. 2009
The Results section (‘Protein degradation by autophagy is enhanced during cellular aging’; page unavailable) reports increased autophagic flux in aged cells, supporting a link between cellular aging and autophagy. But the Discussion explicitly says the studied cells were ‘aged but pre-senescent,’ so this paper does not establish the claimed association with senescence across various cell systems. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDuring replicative senescence in HDFs, there is a gradual shift in degradation pathway for polyubiquitinated proteins from proteasome to autophagy.
“Gamerdinger et al. (2009) showed a gradual shift in the degradation pathway for polyubiquitinated proteins from the proteasome pathway to autophagy during replicative senescence in HDFs.”
From Cellular senescence and its effector programs (2014) · cites this paper as Gamerdinger et al. 2009
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“so-called cytoplasmic punctae that can be co-labeled with LC3 as well as WIPI1 [18].”
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Autophagy Impairment Induces Premature Senescence in Primary Human Fibroblasts
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“In addition, the decline of the p62 monomer, which is required for the transport of poly-ubiquitinated proteins into the autophagosome, may induce defective clearance and accumulation of polyubiquitinated proteins in cells as previously reported [39].”
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Functional Modules of the Proteostasis NetworkPreprint
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“Aggregated proteins accumulate in ubiquitin positive deposits to which the autophagic machinery is recruited by chaperones in a process known as chaperone-assisted selective autophagy (CASA) (Carra et al. 2008; Gamerdinger et al. 2009; Arndt et al. 2010).”
BackgroundSelf-citationShaping proteostasis at the cellular, tissue, and organismal level
Sala, A. J., Bott, L. C., & Morimoto, R. I. (2017) · The Journal of Cell Biology · doi:10.1083/jcb.201612111 · Cited by 250 · see citing works
“Cofactors with tetratricopeptide repeat (TPR) domains, such as CHIP (C terminus of Hsp70 interacting protein, also known as STUB1), and BAG domain–containing nucleotide exchange factors interact with the HSP70/HSP90 machinery and direct substrates for degradation by the UPS or lysosomes (Agarraberes and Dice, 2001; De…”
BackgroundHsp70 – a master regulator in protein degradation
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Protein oxidation in aging and the removal of oxidized proteins
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“[320] Gamerdinger M, Hajieva P, Kaya AM, Wolfrum U, Hartl FU, Behl C.”
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“Selectivity is provided by ubiquitin-binding adaptor proteins p62/SQSTM1, NBR1, and HDAC6 (15,16), which link ubiquitinated cargo to LC3B, and in the case of HDAC6, additionally to dynein-dynactin motor proteins (16-20).”
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“Senescent cells also upregulate autophagy (Gamerdinger et al., 2009; Young et al., 2009), an organelle recycling process, and this might contribute to remodeling of senescent cells and provide the raw materials for altered biosynthetic processes.”
The nucleotide exchange factors of Hsp70 molecular chaperones
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“Interestingly, Bag3 is the only stress-inducible BAG-domain protein (Franceschelli et al., 2008), and its increased abundance might tip the balance from proteasomal to lysosomal degradation (Gamerdinger et al., 2009).”
BackgroundSelective Autophagy in Cancer Development and Therapy
Đikić, I., Johansen, T., & Kirkin, V. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-4027 · Cited by 212 · see citing works
“It is suggested that the shift in BAG1-BAG3 expression ratio during cell senescence can activate autophagy in aged cells (23).”
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Proteostasis in cardiac health and disease
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The ubiquitin-proteasome system and autophagy: Coordinated and independent activities
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The Role of the Multifunctional BAG3 Protein in Cellular Protein Quality Control and in Disease
Stürner, E., & Behl, C. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00177 · Cited by 194 · see citing works
“An increased cellular BAG3 level was additionally verified during cellular aging in neuronal cells as well as in lung fibroblasts (Gamerdinger et al., 2009).”
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Identification of the key structural motifs involved in HspB8/HspB6–Bag3 interaction
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Mechanisms tailoring the expression of heat shock proteins to proteostasis challenges
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Chaperone-assisted degradation: multiple paths to destruction
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Heat shock proteins as potential targets for protective strategies in neurodegeneration
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“The complex comprises the molecular chaperones HSPA8/HSC70 and HSPB8/HSP22, coupled by the cochaperone BAG3 that is essential for the initiation of CASA.(3,14,15) BAG3 cooperates with the HSPA8-associated ubiquitin ligase STUB1/CHIP and its partner UBE2D (ubiquitin-conjugating enzyme E2D) in the ubiquitination of chap…”
BackgroundRauch, J. N., & Gestwicki, J. E. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.521997 · Cited by 167 · see citing works
“BAG1 is involved in multiple processes, including proteasomal degradation (32–34), whereas BAG3 is linked to autophagy (37), and BAG2 coordinates the removal of protein aggregates (36).”
BackgroundHsp70 chaperone: a master player in protein homeostasis
Fernández-Fernández, M. R., & Valpuesta, J. (2018) · F1000Research · doi:10.12688/f1000research.15528.1 · Cited by 162 · see citing works
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Small Heat Shock Proteins, Big Impact on Protein Aggregation in Neurodegenerative Disease
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BAG3 induces the sequestration of proteasomal clients into cytoplasmic puncta
Minoia, M., Boncoraglio, A., Vinet, J., Morelli, F., Brunsting, J. F., Poletti, A., Schipper-Krom, S., Reits, E. A., Kampinga, H. H., & Carra, S. (2014) · Autophagy · doi:10.4161/auto.29409 · Cited by 159 · see citing works
“First, we investigated the effect of proteasomal inhibition on the subcellular localization of BAG3.”
BackgroundInfluentialThe Life and Death of a Plant Cell
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MiR-34 modulates Caenorhabditis elegans lifespan via repressing the autophagy gene atg9
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The role of molecular chaperones in human misfolding diseases
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“autophagic degradation pathway during the ageing process [27].”
BackgroundSelf-citationAutophagy Suppresses Age-Dependent Ischemia and Reperfusion Injury in Livers of Mice
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“More recent evidence has shown that the ratio of the BAG domain-containing proteins BAG1 and BAG3 may shift protein degradation towards different pathways [59] and thus regulate proteostasis.”
BackgroundThe remarkable multivalency of the Hsp70 chaperones
Zuiderweg, E. R. P., Hightower, L. E., & Gestwicki, J. E. (2017) · Cell Stress and Chaperones · doi:10.1007/s12192-017-0776-y · Cited by 137 · see citing works
“BAG1 and BAG3 represent key players of cellular by stimulating the turnover of polyubiquitinated proteins by proteasomal and autophagic degradation pathways, respectively (Gamerdinger et al. 2009).”
Loss-of-function mutations in co-chaperone BAG3 destabilize small HSPs and cause cardiomyopathy
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“As it has also been reported that BAG3 is involved in autophagy (37), we next investigated how the loss of BAG3 might affect autophagic flux by examining the levels of the autophago someassociated protein light chain 3B (LC3B) (38), which is present in cytosolic form (LC3B-I) until it becomes targeted to nascent autop…”
The chaperone-assisted selective autophagy complex dynamics and dysfunctions
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Protein Disaggregation in Multicellular Organisms
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Pharmacological Targeting of the Hsp70 Chaperone
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“In addition to being implicated in cancer, protein misfolding disorders and infection, Hsp70 and its co-chaperones have been associated with numerous other diseases, including Crohn’s disease [130], Behcet’s disease [131], ischemic stroke [132] and ALS [133], and this chaperone also plays roles in normal aging [134, 1…”
Autophagy: links with the proteasome
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“Since all studies on the BAG1/BAG3 ratio and BAG3-mediated autophagy have come from the animal kingdom [206], it is worth asking if such modulation of the PQC system is also present in plants where the BAG protein family is conserved [211–215].”
BackgroundThe lysosomal proteome of senescent cells contributes to the senescence secretome
Rovira, M., Sereda, R., Pladevall‐Morera, D., Ramponi, V., Marín, I., Maus, M., Madrigal‐Matute, J., Díaz, A., Garcı́a, F., Muñoz, J., et al. (2022) · Aging Cell · doi:10.1111/acel.13707 · Cited by 125 · see citing works
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“Furthermore, p62 protein, a selective substrate of autophagy, and the high molecular weight forms of p62 (33) significantly accumulated in cKO mice.”
BackgroundAutophagy in Age-Associated Neurodegeneration
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“Interestingly, BAG3 is associated with p62/SQSTM1, which mediates the interaction with the LC3-II-marked phagophores [168,171].”
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“Although R-GFP is an N-end rule substrate, HSC70 may also be involved in its proteasomal degradation, as knockdown of BAG1, a HSC70 co-chaperone that mediates the interaction between HSC70 and proteasome, caused accumulation of R-GFP (Gamerdinger et al , 2009).”
Autophagy in regulation of Toll-like receptor signaling
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The role of heat shock proteins and co-chaperones in heart failure
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Quality Control Against Misfolded Proteins in the Cytosol: A Network for Cell Survival
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Sulforaphane enhances progerin clearance in H utchinson– G ilford progeria fibroblasts
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“Cells rely on two proteolytic systems to maintain proteostasis: the lysosomal system (or autophagy) and the ubiquitin – proteasome system (Gamerdinger et al. , 2009).”
InfluentialRadiation-induced autophagy: mechanisms and consequences
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“Bag1 helps in the removal of ubiquitinated proteins via UPS, whereas Bag3 helps in the autophagic removal of degraded proteins [36].”
BackgroundThe ubiquitin-proteasome system in cardiac proteinopathy: a quality control perspective
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“BAG3 recruits the autophagic system by teaming up with p62/SQSTM.(55) It seems that concentrating”
BackgroundInfluentialGamerdinger, M., Carra, S., & Behl, C. (2011) · Journal of Molecular Medicine · doi:10.1007/s00109-011-0795-6 · Cited by 113 · see citing works
“Interestingly, the decreased proteasomal activation and the increased macroautophagy activation in aged cells/tissue have been correlated with decreased levels of BAG1 and increased levels of BAG3 [ 21 ].”
InfluentialSelf-citationIKKγ protein is a target of BAG3 regulatory activity in human tumor growth
Ammirante, M., Rosati, A., Arra, C., Basile, A. M., Falco, A., Festa, M., Pascale, M. C., d’Avenia, M., Marzullo, L., Belisario, M. A., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0907696107 · Cited by 111 · see citing works
“Moreover, BAG3 is known to play a role in other cellular processes, such as autophagy (50, 51) and cell motility (46–48), that also involve the NF-κB pathway (52–55).”
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BAG3 facilitates the clearance of endogenous tau in primary neurons
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Molecular chaperones and neuronal proteostasis
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“autophagosome receptor p62 [34], enabling the recruitment of Hsp70-Hsp22-Bag3 bound cargo into the autophagosome for degradation.”
BackgroundMolecular Chaperones: A Double-Edged Sword in Neurodegenerative Diseases
Tittelmeier, J., Nachman, E., & Nussbaum-Krammer, C. I. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.581374 · Cited by 107 · see citing works
“Also, TDP-43 is degraded by chaperone-assisted selective autophagy (CASA), where the sHsp HSPB8 works together with HSC70, BAG3, and CHIP to deliver substrates to autophagy.”
BackgroundInfluentialProtein Homeostasis, Aging and Alzheimer’s Disease
Morawe, T., Hiebel, C., Kern, A., & Behl, C. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8246-0 · Cited by 107 · see citing works
“This correlates with decreased levels of BAG1 and increased levels of BAG3 in aged cells, an age-related BAG1/BAG3 switch that serves as an induction control of the macroautophagic pathway (BAG3-mediated selective macroautophagy) and may be considered as a backup of the UPS in PQC ([40, 72]).”
BackgroundInfluentialSelf-citation
- Authors
- Gamerdinger, M., Hajieva, P., Kaya, A. M., Wolfrum, U., Hartl, F. U., & Behl, C.
- Affiliations
- Johannes Gutenberg University Mainz (DE)
- Max Planck Institute of Biochemistry (DE)
- Corresponding author
- Behl, Christian
- Venue
- The EMBO Journal
- Published
- 2009-02-19
- Volume
- 28
- Issue
- 7
- Pages
- 889-901
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC2647772
- OpenAlex
- W2094186182
- Cited by
- 522
- References
- 42
- Citations by year
- 2026: 20 · 2025: 20 · 2024: 20 · 2023: 24 · 2022: 33 · 2021: 32 · 2020: 25 · 2019: 23 · 2018: 37 · 2017: 47 · 2016: 38 · 2015: 33 · 2014: 32 · 2013: 35 · 2012: 25
- FWCI
- 23.16
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- protein quality control, aging, BAG3, BAG-1, macroautophagy, autophagy, polyubiquitinated proteins, proteasome, p62, LC3-II, cathepsin activity, neuronal aging, brain aging, proteostasis, protein aggregation, oxidative stress
- MeSH terms
- Animals, Autophagy, DNA-Binding Proteins, Humans, Immunohistochemistry, Transcription Factors, Cellular Senescence, Rats, Sprague-Dawley, Microscopy, Electron, Transmission, Proteasome Endopeptidase Complex, Adaptor Proteins, Signal Transducing, Apoptosis Regulatory Proteins, Mice, Rats
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