A novel endoplasmic reticulum adaptation is critical for the long-lived Caenorhabditis elegans rpn-10 proteasomal mutant |
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| Affiliation: | 1. Barshop Institute for Longevity and Aging Studies, UT Health San Antonio (UTHSCSA), SA, TX, United States of America;2. Department of Cell Systems and Anatomy, UTHSCSA, SA, TX, United States of America;3. Division of Geriatrics, Gerontology, and Palliative Medicine, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States of America;1. Department of Cell Biology and Genetics, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China;2. State Key Laboratory of Proteomics, Beijing Proteome Reesearch Center, National Center for Protein Sciences Beijing, Research Unit of Proteomics & Research and Development of New Drug of Chinese Academy of Medical Sciences, Institute of Lifeomics, Beijing 102206, China;3. Anhui Medical University School of Basic Medicine, Hefei 230032, Anhui, China;4. Department of Biomedicine, School of Medicine, Guizhou University, Guiyang 550025, China;5. Department of Toxicology, School of Public Health, China Medical University, Shenyang, 110122, PR China;1. Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, Jiangsu 215123, China;2. Department of Pharmacy, Medical Center of Soochow University, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, Jiangsu 215123, China;1. Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Soochow University, Suzhou, Jiangsu 215123, PR China;2. Key Laboratory of Pesticides & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, Hubei 430079, PR China;3. School of Biology and Basic Medical Science, Soochow University, Suzhou, Jiangsu 215021, PR China |
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| Abstract: | The loss of proteostasis due to reduced efficiency of protein degradation pathways plays a key role in multiple age-related diseases and is a hallmark of the aging process. Paradoxically, we have previously reported that the Caenorhabditis elegans rpn-10(ok1865) mutant, which lacks the RPN-10/RPN10/PSMD4 subunit of the 19S regulatory particle of the 26S proteasome, exhibits enhanced cytosolic proteostasis, elevated stress resistance and extended lifespan, despite possessing reduced proteasome function. However, the response of this mutant against threats to endoplasmic reticulum (ER) homeostasis and proteostasis was unknown. Here, we find that the rpn-10 mutant is highly ER stress resistant compared to the wildtype. Under unstressed conditions, the ER unfolded protein response (UPR) is activated in the rpn-10 mutant as signified by increased xbp-1 splicing. This primed response appears to alter ER homeostasis through the upregulated expression of genes involved in ER protein quality control (ERQC), including those in the ER-associated protein degradation (ERAD) pathway. Pertinently, we find that ERQC is critical for the rpn-10 mutant longevity. These changes also alter ER proteostasis, as studied using the C. elegans alpha-1 antitrypsin (AAT) deficiency model, which comprises an intestinal ER-localised transgenic reporter of an aggregation-prone form of AAT called ATZ. The rpn-10 mutant shows a significant reduction in the accumulation of the ATZ reporter, thus indicating that its ER proteostasis is augmented. Via a genetic screen for suppressors of decreased ATZ aggregation in the rpn-10 mutant, we then identified ecps-2/H04D03.3, a novel ortholog of the proteasome-associated adaptor and scaffold protein ECM29/ECPAS. We further show that ecps-2 is required for improved ER proteostasis as well as lifespan extension of the rpn-10 mutant. Thus, we propose that ECPS-2-proteasome functional interactions, alongside additional putative molecular processes, contribute to a novel ERQC adaptation which underlies the superior proteostasis and longevity of the rpn-10 mutant. |
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