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CHIP Deficiency Decreases Longevity, with Accelerated Aging Phenotypes Accompanied by Altered Protein Quality Control
Open accessAbstract
During the course of biological aging, there is a gradual accumulation of damaged proteins and a concomitant functional decline in the protein degradation system. Protein quality control is normally ensured by the coordinated actions of molecular chaperones and the protein degradation system that collectively help to maintain protein homeostasis. The carboxyl terminus of Hsp70-interacting protein (CHIP), a ubiquitin ligase/cochaperone, participates in protein quality control by targeting a broad range of chaperone substrates for proteasome degradation via the ubiquitin-proteasome system, demonstrating a broad involvement of CHIP in maintaining cytoplasmic protein quality control. In the present study, we have investigated the influence that protein quality control exerts on the aging process by using CHIP-/- mice. CHIP deficiency in mice leads to a markedly reduced life span, along with accelerated age-related pathophysiological phenotypes. These features were accompanied by indications of accelerated cellular senescence and increased indices of oxidative stress. In addition, CHIP-/- mice exhibit a deregulation of protein quality control, as indicated by elevated levels of toxic oligomer proteins and a decline in proteasome activity. Taken together, these data reveal that impaired protein quality control contributes to cellular senescence and implicates CHIP-dependent quality control mechanisms in the regulation of mammalian longevity in vivo.
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“studies in CHIP defective mice also support an important role for the UPS in longevity and health-span (Min et al., 2008)”
From Protein Homeostasis and Aging: the importance of exquisite quality control (2011) · cites this paper as Min et al., 2008
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“Also, mutant mice deficient in a co-chaperone of the heat-shock family exhibit accelerated-aging phenotypes, whereas long-lived mouse strains show a marked up-regulation of some heat-shock proteins (Min et al., 2008; Swindell et al., 2009).”
From The Hallmarks of Aging (2013) · cites this paper as Min et al., 2008
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BackgroundKettern, N., Rogon, C., Limmer, A., Schild, H., & Höhfeld, J. (2011) · PLoS ONE · doi:10.1371/journal.pone.0016398 · Cited by 60
“Moreover, CHIP deficient mice show an increased sensitivity to oxidative damage [47].”
BackgroundKireev, R. A., Vara, E., Viña, J., & Tresguerres, J. A. F. (2014) · AGE · doi:10.1007/s11357-014-9707-3 · Cited by 59
“This condition caused gradual accumulation of damaged proteins leading to a functional decline in the brain’s endogenous defence system (Rumora et al. 2007; Min et al. 2008) and leading to the activation of stress kinases (JNK and p38 MAPK) (Gabai et al.”
BackgroundChaperone-assisted E3 ligase CHIP: A double agent in cancer
Kumar, S., Basu, M., & Ghosh, M. K. (2021) · Genes & Diseases · doi:10.1016/j.gendis.2021.08.003 · Cited by 59
“It has been reported that in STUB1 deficient mice, lagging related biomarkers are increased due to accumulation of toxic proteins.(277) Expression of leucine rich repeat kinase-2 (LRRK2) is high in STUB1 KO mouse model of PD.”
BackgroundThe E3 ubiquitin ligase CHIP in normal cell function and in disease conditions
Wang, T., Wang, W., Wang, Q., Xie, R., LANDAY, A. L., & Chen, D. (2019) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14206 · Cited by 58
Kevei, É., Pokrzywa, W., & Hoppe, T. (2017) · FEBS Letters · doi:10.1002/1873-3468.12750 · Cited by 53
Role of S5b/PSMD5 in Proteasome Inhibition Caused by TNF-α/NFκB in Higher Eukaryotes
Shim, S. M., Lee, W., Kim, Y., Chang, J. W., Song, S., & Jung, Y. (2012) · Cell Reports · doi:10.1016/j.celrep.2012.07.013 · Cited by 49
Zhao, T., Hong, Y., Yin, P., Li, S., & Li, X. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1710549114 · Cited by 54
“Mice with CHIP deficiency show increased levels of toxic oligomer proteins and decreased proteasomal activity (6).”
BackgroundmTORC1 Links Protein Quality and Quantity Control by Sensing Chaperone Availability
Qian, S., Zhang, X., Sun, J., Bennink, J. R., Yewdell, J. W., & Patterson, C. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.120295 · Cited by 52
Self-citationKim, S., Grenert, J. P., Patterson, C., & Correia, M. A. (2016) · Scientific Reports · doi:10.1038/srep29423 · Cited by 51
Self-citationThe roles of ubiquitination in extrinsic cell death pathways and its implications for therapeutics
Seo, J., Kim, M. W., Bae, K., Lee, S. C., Song, J., & Lee, E. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.11.012 · Cited by 48
Autophagy and the ubiquitin-proteasome system in cardiac dysfunction.
Zheng, Q., & Wang, X. (2010) · PubMed · Cited by 49
Hsp70 and Hsp90 oppositely regulate TGF-β signaling through CHIP/Stub1
Shang, Y., Xu, X., Duan, X., Guo, J., Wang, Y., Ren, F., He, D., & Chang, Z. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.02.124 · Cited by 48
Molecular chaperones as regulators of cell death
Hishiya, A., & Takayama, S.-I. J. (2008) · Oncogene · doi:10.1038/onc.2008.314 · Cited by 48
Protein Homeostasis at the Plasma Membrane
Apaja, P. M., & Lukács, G. L. (2014) · Physiology · doi:10.1152/physiol.00058.2013 · Cited by 46
“These observations with the modest phenotypic manifestation of the CHIP knockout mouse (87) suggest that a complex network of QC E3 ligases has evolved to maintain PM proteostasis with overlapping substrate specificity.”
BackgroundHuang, C., Kuo, W., Lo, J., Ho, T., Pai, P., Chiang, S., Chen, P., Tsai, F.-J., Tsai, C., & Huang, C. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.356 · Cited by 46
Ubiquitin Ligases in Longevity and Aging Skeletal Muscle
Hughes, D. C., Baehr, L. M., Waddell, D. S., Sharples, A. P., & Bodine, S. C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23147602 · Cited by 45
“In whole body knockout mice, CHIP deficiency significantly reduced mammalian lifespan and was accompanied by reduced proteasome activity in muscle and liver tissues [36].”
BackgroundA CHIPotle in physiology and disease
Paul, I., & Ghosh, M. K. (2014) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2014.10.027 · Cited by 45
Woo, C.-H., Le, N., Shishido, T., Chang, E. B., Lee, H., Heo, K., Mickelsen, D. M., Lu, Y., McClain, C., Spangenberg, T., et al. (2010) · The FASEB Journal · doi:10.1096/fj.10-162636 · Cited by 44
Self-citationConnecting chaperone-mediated autophagy dysfunction to cellular senescence
Moreno-Blas, D., Gorostieta-Salas, E., & Castro‐Obregón, S. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.11.001 · Cited by 42
Luan, H., Mohapatra, B. C., Bielecki, T. A., Mushtaq, I., Mirza, S., Jennings, T. A., Clubb, R. J., An, W., Ahmed, D., Ansari, R. E., et al. (2018) · Cancer Research · doi:10.1158/0008-5472.can-16-2140 · Cited by 42
Willis, M. S., Min, J., Wang, S., McDonough, H., Lockyer, P. P., Wadosky, K. M., & Patterson, C. (2013) · Cell Biochemistry and Function · doi:10.1002/cbf.2962 · Cited by 40
“This may account for the disproportionate increase in HW/BW versus the cross-sectional areas of the CHIP / and wild-type mice, which has previously been reported.(29) The running performance of both CHIP / and wild-type mice improved during the course of voluntary running (Supplemental Figure 1A).”
BackgroundMethodInfluentialSelf-citationZhou, Y., Zhu, Y., Zhang, L., Wu, T., Wu, T., Zhang, W., Decker, A. M., He, J., Liu, J., Wu, Y., et al. (2016) · Stem Cells · doi:10.1002/stem.2321 · Cited by 41
Chronic obstructive pulmonary disease and the hallmarks of aging
Bailey, K. L., Kukrety, S., & Parekh, J. D. (2018) · Lung India · doi:10.4103/lungindia.lungindia_266_17 · Cited by 44
“[41] Genetically modified mice deficient in HSP demonstrates accelerated aging.[42] Function of the proteolytic systems also diminishes with aging.”
BackgroundSpinocerebellar ataxia type 48: last but not least
Michele, G. D., Galatolo, D., Barghigiani, M., Iacovo, D. D., Trovato, R., Tessa, A., Salvatore, E., Filla, A., Michele, G. D., & Santorelli, F. (2020) · Neurological Sciences · doi:10.1007/s10072-020-04408-3 · Cited by 34
Romanucci, M., & Salda, L. D. (2015) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2015/940131 · Cited by 43
E6-AP association promotes SOD1 aggresomes degradation and suppresses toxicity
Mishra, A., Maheshwari, M., Chhangani, D., Fujimori-Tonou, N., Endo, F., Joshi, A. P., Jana, N. R., & Yamanaka, K. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.08.016 · Cited by 40
Germain, D. (2008) · Molecular Microbiology · doi:10.1111/j.1365-2958.2008.06502.x · Cited by 43
“Since protein oxidation increases with age, while proteasome activity decreases with age (Berlett and Stadtman, 1997; Min et al., 2008; Morimoto, 2008), if correct this possibility would suggest that proteasome activators in combination with antioxidants may represent a novel anti-ageing strategy.”
BackgroundRonnebaum, S. M., Patterson, C., & Schisler, J. C. (2014) · Molecular Endocrinology · doi:10.1210/me.2014-1180 · Cited by 39
“Additionally, our laboratory recently reported on a novel interaction between AMPK and C terminus of heat shock protein 70-interacting protein (CHIP), an E3 ubiquitin ligase that mediates protein quality control during acute and chronic stress (66, 67).”
BackgroundSelf-citationThe E3 Ligase CHIP Mediates p21 Degradation to Maintain Radioresistance
Biswas, K., Sarkar, S., Du, K., Brautigan, D. L., Abbas, T., & Larner, J. M. (2017) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-16-0466 · Cited by 38
“Consistently, CHIP-deficient mice (chip / ) exhibit reduced life span with accelerated aging phenotypes including osteoporosis, cellular senescence, and accumulation of oxidized lipids (10).”
BackgroundNeuronal Preconditioning Requires the Mitophagic Activity of C-terminus of HSC70-Interacting Protein
Lizama, B. N., Palubinsky, A. M., Raveendran, V. A., Moore, A. M., Federspiel, J. D., Codreanu, S. G., Liebler, D. C., & McLaughlin, B. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.0699-18.2018 · Cited by 37
“Because chronic loss of CHIP causes profound changes in the proteome and intracellular milieu (Min et al., 2008; Palubinsky et al., 2015), we chose to acutely deplete rat primary neurons of endogenous CHIP using siRNA to test this hypothesis.”
BackgroundMethodHuang, P., Kuo, W., Shen, C.-Y., Chen, Y.-F., Lin, Y.-M., Ho, T., Padma, V. V., Lo, J., Huang, K. C., & Huang, C. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17091588 · Cited by 37
“Moreover, CHIP exerts its cardioprotective effect via regulating protein stability during heart failure [67,68].”
Background
Metadata
- Authors
- Min, J.-N., Whaley, R. A., Sharpless, N. E., Lockyer, P., Portbury, A. L., & Patterson, C.
- Affiliations
- Carolina Cardiovascular Biology Center
- UNC Lineberger Comprehensive Cancer Center (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Patterson, Cam
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2008-06-01
- Volume
- 28
- Issue
- 12
- Pages
- 4018-4025
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC2423116
- OpenAlex
- W2143659623
- Cited by
- 256
- References
- 49
- Citations by year
- 2026: 8 · 2025: 5 · 2024: 5 · 2023: 12 · 2022: 8 · 2021: 16 · 2020: 20 · 2019: 14 · 2018: 18 · 2017: 19 · 2016: 17 · 2015: 11 · 2014: 22 · 2013: 19 · 2012: 14
- FWCI
- 4.57
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- American Heart Association
- National Institutes of Health (5r01gm061728-12)
- National Institute on Aging (AG 024282, P01 AG 024282)
- National Heart, Lung, and Blood Institute (HL 65619, R01HL065619, R37HL065619)
- National Institute of General Medical Sciences (GM-61728, R01-GM061728)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- 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
- CHIP, protein quality control, aging, longevity, accelerated aging, cellular senescence, proteasome activity, ubiquitin-proteasome system, oxidative stress, protein aggregation, proteostasis
- MeSH terms
- Aging, Animals, Brain, Cytoplasm, Lipids, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, Oxygen, Phenotype, Cellular Senescence, Molecular Chaperones, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, Mice
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