Proteasomal adaptation to environmental stress links resistance to proteotoxicity with longevity in Caenorhabditis elegans
Open accessAbstract
The burden of protein misfolding is believed to contribute to aging. However, the links between adaptations to conditions associated with protein misfolding and resistance to the time-dependent attrition of cellular function remain poorly understood. We report that worms lacking aip-1 , a homologue of mammalian AIRAP (arsenic-inducible proteasomal 19S regulatory particle-associated protein), are not only impaired in their ability to resist exposure to arsenite but also exhibit shortened lifespan and hypersensitivity to misfolding-prone proteins under normal laboratory conditions. Mammals have a second, constitutively expressed AIRAP-like gene (AIRAPL) that also encodes a proteasome-interacting protein, which shares with AIRAP the property of enhancing peptide accessibility to the proteasome's active site. Genetic rescue experiments suggest that features common to the constitutively expressed worm AIP-1 and mammalian AIRAPL (but missing in the smaller, arsenite-inducible AIRAP) are important to lifespan extension. In worms, a single AIRAP-related protein links proteasomal adaptation to environmental stress with resistance to both proteotoxic insults and maintenance of animal life span under normal conditions.
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Worms lacking AIP-1, a homologue of the regulatory mammalian subunit AIRAP, exhibit shortened lifespan and hypersensitivity to misfolding proteins.
“worms lacking AIP-1, a homologue of the regulatory mammalian subunit AIRAP, exhibit shortened lifespan and hypersensitivity to misfolding proteins (Yun et al., 2008)”
From Protein Homeostasis and Aging: the importance of exquisite quality control (2011) · cites this paper as Yun et al., 2008
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BackgroundInfluentialSelf-citationStructure and Function of the Ubiquitin–Proteasome System
Chondrogianni, N., & Gonos, E. S. (2012) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-397863-9.00002-x · Cited by 30 · see citing works
Miyazaki, Y., Chen, L., Chu, B. W., Swigut, T., & Wandless, T. J. (2015) · eLife · doi:10.7554/elife.07687 · Cited by 28 · see citing works
“At this point, the cocultured cells were then treated with either vehicle or with 30 μM sodium arsenite (Yun et al., 2008), cultured overnight, and analyzed at 24 hr (post appearance of unfolded DD) by flow cytometry.”
MethodWang, X., Cao, M., & Dong, Y. (2016) · Oncotarget · doi:10.18632/oncotarget.10857 · Cited by 27 · see citing works
“However, aging will perturb this regulatory network and decrease the protective capacity of proteostasis [12, 13].”
BackgroundIdentifying Aβ-specific pathogenic mechanisms using a nematode model of Alzheimer's disease
Hassan, W. M., Dostal, V., Huemann, B. N., Yerg, J., & Link, C. D. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.10.016 · Cited by 25 · see citing works
“regulatory component of the 19S proteasome caps (Yun et al., 2008), in the Aβ animals, implicates proteasome dysfunction in Aβ toxicity.”
BackgroundResultHSF-1: Guardian of the Proteome Through Integration of Longevity Signals to the Proteostatic Network
Lázaro‐Peña, M. I., Ward, Z. C., Yang, S., Strohm, A. O., Merrill, A. K., Soto, C. A., & Samuelson, A. V. (2022) · Frontiers in Aging · doi:10.3389/fragi.2022.861686 · Cited by 27 · see citing works
“Multiple studies have shown that loss of proteasome subunits lead to premature aging (Yun et al., 2008; Chondrogianni et al., 2015).”
BackgroundFerguson, A. A., Springer, M. G., & Fisher, A. L. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.01340-09 · Cited by 25 · see citing works
“CAAX motif which is required for function (64).”
BackgroundInfluentialSá‐Moura, B., Funakoshi, M., Tomko, R. J., Dohmen, R. J., Wu, Z., Peng, J., & Hochstrasser, M. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.521088 · Cited by 25 · see citing works
“Moreover, previous studies had shown that AIRAP and AIRAPL, mammalian proteins related to Cuz1, can interact with the 26 S proteasome (40, 41).”
BackgroundInfluentialSignal-peptide-mediated translocation is regulated by a p97–AIRAPL complex
Glinka, T., Alter, J., Braunstein, I., Tzach, L., Sheng, C. W., Shochat, S. G., Edelmann, M. J., Kessler, B. M., & Stanhill, A. (2013) · Biochemical Journal · doi:10.1042/bj20130710 · Cited by 25 · see citing works
Self-citationSteinbach, M. K., Leipert, J., Blurton, C., et al. (2022) · Journal of Proteome Research · doi:10.1021/acs.jproteome.2c00274 · Cited by 22 · see citing works
UPS Activation in the Battle Against Aging and Aggregation-Related Diseases: An Extended Review
Papaevgeniou, N., & Chondrogianni, N. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-3756-1_1 · Cited by 22 · see citing works
Vayndorf, E. M., Scerbak, C., Hunter, S., Neuswanger, J. R., Toth, M., Parker, J., Néri, C., Driscoll, M., & Taylor, B. E. (2016) · npj Aging and Mechanisms of Disease · doi:10.1038/npjamd.2016.1 · Cited by 20 · see citing works
Selective Binding of AIRAPL Tandem UIMs to Lys48-Linked Tri-Ubiquitin Chains
Rahighi, S., Braunstein, I., Ternette, N., Kessler, B. M., Kawasaki, M., Kato, R., Matsui, T., Weiss, T. M., Stanhill, A., & Soichi Wakatsuki, A. (2016) · Structure · doi:10.1016/j.str.2015.12.017 · Cited by 20 · see citing works
“Functional impairment of AIRAPL homologues is linked to the acceleration of ageing and protein aggregation (Yun et al., 2008).”
BackgroundMethodInfluentialSelf-citationHanna, J. W., Waterman, D. P., Isasa, M., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.534032 · Cited by 20 · see citing works
“This protein shows homology to the mammalian proteins AIRAP(3) (arsenite inducible RNAassociated protein) and AIRAP-like protein, as well as Aip-1, which is required for longevity in Caenorhabditis elegans (10, 11).”
BackgroundPredicting protein subcellular location with network embedding and enrichment features
Pan, X., Lü, L., & Cai, Y. (2020) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2020.140477 · Cited by 19 · see citing works
Scomazzon, S. P., Riccio, A., Santopolo, S., Lanzilli, G., Coccia, M., Rossi, A., & Santoro, M. G. (2019) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-19-0243 · Cited by 17 · see citing works
“Differently from the AIRAP worm homologue, aip-1, a gene known to play an important role in preserving animal lifespan and buffering arsenicinduced proteotoxicity, mammals have a second, constitutively expressed, AIRAP-like gene (AIRAPL), recently implicated in myeloid transformation.”
BackgroundInfluentialGenome-Scale Studies of Aging: Challenges and Opportunities
McCormick, M. A., & Kennedy, B. K. (2012) · Current Genomics · doi:10.2174/138920212803251454 · Cited by 16 · see citing works
Life and destruction: ubiquitin-mediated proteolysis in aging and longevity
Hoppe, T. (2010) · F1000 Biology Reports · doi:10.3410/b2-79 · Cited by 13 · see citing works
“elegans lacking proteasomal subunits or AIP-1 (ASK-interacting protein 1, a regulator that is important for proteasomal adaptation to proteotoxic stress conditions) exhibit a shortened lifespan [9,10].”
BackgroundCandidate Genes That Affect Aging Through Protein Homeostasis
Argon, Y., & Gidalevitz, T. (2015) · Advances in experimental medicine and biology · doi:10.1007/978-1-4939-2404-2_2 · Cited by 12 · see citing works
The role of RNF149 in the pre-emptive quality control substrate ubiquitination
Legesse, A., Kaushansky, N., Braunstein, I., Saad, H., Lederkremer, G. Z., Navon, A., & Stanhill, A. (2023) · Communications Biology · doi:10.1038/s42003-023-04763-9 · Cited by 10 · see citing works
Self-citationNAD+ and metabolic regulation of age-related proteoxicity: A possible role for methylglyoxal?
Hipkiss, A. R. (2010) · Experimental Gerontology · doi:10.1016/j.exger.2010.03.006 · Cited by 10 · see citing works
“increase the likelihood of ROS generation which could compromise lifespan (Yun et al., 2008).”
Orenstein, S. J., & Cuervo, A. M. (2009) · Springer eBooks · doi:10.1007/978-90-481-3465-6_10 · Cited by 9 · see citing works
Activators of the 26S proteasome when protein degradation increases
Lee, D. (2025) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01385-x · Cited by 9 · see citing works
Endoplasmic Reticulum Homeostasis and Stress Responses in Caenorhabditis elegans
Lee, S.-K. (2021) · Progress in molecular and subcellular biology · doi:10.1007/978-3-030-67696-4_13 · Cited by 8 · see citing works
Ahmad, S., Arif, B., Akram, Z., Ahmed, M. W., Khan, A. U., Hussain, M. Z., Rahman, F., Kayani, M. A., & Mahjabeen, I. (2020) · Environmental Science and Pollution Research · doi:10.1007/s11356-019-07422-x · Cited by 6 · see citing works
Translating protein phosphatase research into treatments for neurodegenerative diseases
Sundaram, J. R., Lee, I. C. J., & Shenolikar, S. (2017) · Biochemical Society Transactions · doi:10.1042/bst20160157 · Cited by 5 · see citing works
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Tong, H., Li, W., Yuan, P., et al. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.111026 · Cited by 4 · see citing works
The proteasome as a drug target for treatment of parasitic diseases
Liu, L. J., O’Donoghue, A. J., & Caffrey, C. R. (2024) · Advances in Parasitology/Advances in parasitology · doi:10.1016/bs.apar.2024.04.001 · Cited by 4 · see citing works
Santiago‐Fernández, O., Osorio, F. G., & López-Otı́n, C. (2016) · Experimental Hematology · doi:10.1016/j.exphem.2016.04.004 · Cited by 4 · see citing works
He, L., Zhang, H.-R., Di, W., Li, F., Wang, C., Yang, X., Liu, X., & Hu, M. (2023) · Parasites & Vectors · doi:10.1186/s13071-023-05676-6 · Cited by 3 · see citing works
Kunz, P., Lehmann, C., & Pohl, C. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.619596 · Cited by 3 · see citing works
Protein clearance mechanisms and their demise in age-related neurodegenerative diseases
Sáez, I., & Vı́lchez, D. (2015) · AIMS molecular science · doi:10.3934/molsci.2015.1.1 · Cited by 2 · see citing works
“Accordingly, genetic or chemical enhancement of proteasome function and autophagic potential decreases the loading of aberrant proteins and ameliorates the symptoms and incidence of age-related disorders [140,141,161,162].”
BackgroundProtein metabolism and lifespan in Caenorhabditis elegans.
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Invertebrate Models in Arsenic Research
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Structural variant selection for high-altitude adaptation using single-molecule long-read sequencingPreprint
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Modulation of host proteostasis by Prevotella corporis via induction of the heat shock response
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“We also observed induction of autophagy-associated genes, including bec-1 and aip-1 , which promote protein clearance and survival under stress, 47,48 and are implicated in Alzheimer’s disease pathology, 49,50 further supporting the role of P. corporis in enhancing multiple proteostasis arms.”
Protein Quality Control Coming of Age
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The novel tumor suppressor AIRAPL regulates IGF1R proteostasis
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The Effects of Aging on Proteasome Activity, Assembly, and Abundance in C. elegans
Joyce, D. (2012) · eScholarship (California Digital Library)
Multi-omic analysis of the aging mouse brain
Kluever, V. (2021) · doi:10.53846/goediss-9022
He, L., Zhang, H.-R., Di, W.-D., Li, F.-F., Wang, C.-Q., Yang, X., Liu, X.-F., & Hu, M. (2023) · Figshare · doi:10.6084/m9.figshare.22620454
- Authors
- Yun, C., Stanhill, A., Yang, Y., Zhang, Y., Haynes, C. M., Xu, C.-F., Neubert, T. A., Mor, A., Philips, M. R., & Ron, D.
- Affiliations
- *The Kimmel Center for Biology and Medicine at the Skirball Institute for Biomolecular Medicine,
- Technion – Israel Institute of Technology (IL)
- New York University (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-05-13
- Volume
- 105
- Issue
- 19
- Pages
- 7094-7099
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2383958
- OpenAlex
- W2024324790
- Semantic Scholar
- e2c3b7cbbde14671f6733152b88976afcbe8d571
- Cited by
- 98
- References
- 27
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 5 · 2022: 2 · 2021: 4 · 2020: 5 · 2019: 2 · 2018: 2 · 2017: 3 · 2016: 9 · 2015: 7 · 2014: 10 · 2013: 3 · 2012: 9
- FWCI
- 3.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1s10rr017990-01)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-47119, R37DK047119, F32-DK61179, R01DK047119, F32DK061179)
- National Institute of Neurological Disorders and Stroke (NS050276, P30NS050276)
- National Institute of Environmental Health Sciences (ES 08681, R01ES008681)
- National Center for Research Resources (RR017990)
- 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 › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- proteasome, protein misfolding, proteotoxicity, lifespan extension, aging, arsenite resistance, 19S regulatory particle, Caenorhabditis elegans, genetic rescue, stress adaptation
- MeSH terms
- Adaptation, Physiological, Animals, Cell Line, Endoplasmic Reticulum, Environment, Humans, Intracellular Membranes, Longevity, Phenotype, Protein Binding, RNA-Binding Proteins, Caenorhabditis elegans, Sequence Homology, Amino Acid, Protein Folding, Arsenites, Caenorhabditis elegans Proteins, Proteasome Endopeptidase Complex, Mice
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