ACS Publications. Most Trusted. Most Cited. Most Read
My Activity

Overexpression of CD38 Decreases Cellular NAD Levels and Alters the Expression of Proteins Involved in Energy Metabolism and Antioxidant Defense

View Author Information
MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing 100084, China
Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing 100020, China
*Tel: 8610-62790498. Fax: 8610-62797154. E-mail: [email protected]
Cite this: J. Proteome Res. 2014, 13, 2, 786–795
Publication Date (Web):December 2, 2013
Copyright © 2013 American Chemical Society

    Article Views





    Read OnlinePDF (2 MB)
    Supporting Info (1)»


    Abstract Image

    Nicotinamide adenine dinucleotide (NAD) is a coenzyme found in all living cells and mediates multiple cellular signaling pathways. In the present study, a 35% decrease of cellular NAD level is achieved by stable expression of the N-terminal truncated CD38, a NAD hydrolase. CD38-expressing (CD38(+)) cells have the lower growth rate and are more susceptive to oxidative stress than the wild type cells and empty vector-transfected (CD38(−)) cells. Quantitative proteomic analysis shows that 178 proteins are down-regulated in CD38(+) cells, which involve in diverse cellular processes including glycolysis, RNA processing and protein synthesis, antioxidant, and DNA repair. Down regulation of six selected proteins is confirmed by Western blotting. However, down-regulation of mRNA expressions of genes associated with glycolysis, antioxidant, and DNA repair is less significant than the corresponding change in protein expression, suggesting the low NAD level impairs the protein translational machinery in CD38(+) cells. Down-regulation of antioxidant protein and DNA-repair protein expression contributes to the susceptibility of CD38(+) cells to oxidative stress. Taken together, these results demonstrate that CD38(+) cells are a useful model to study effects of the cellular NAD levels on cellular processes and establish a new linker between cellular NAD levels and oxidative stress.

    Supporting Information

    Jump To

    Supplementary figures, tables, and data. This material is available free of charge via the Internet at

    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system:

    Cited By

    This article is cited by 36 publications.

    1. Changmei Yang, Tianxiang Wang, Songbiao Zhu, Zhaoyun Zong, Chengting Luo, Yujiao Zhao, Jing Liu, Ting Li, Xiaohui Liu, Chongdong Liu, Haiteng Deng. Nicotinamide N-Methyltransferase Remodeled Cell Metabolism and Aggravated Proinflammatory Responses by Activating STAT3/IL1β/PGE2 Pathway. ACS Omega 2022, 7 (42) , 37509-37519.
    2. Huan Liu, Siying Li, Xiaohui Liu, Yuling Chen, Haiteng Deng. SIRT3 Overexpression Inhibits Growth of Kidney Tumor Cells and Enhances Mitochondrial Biogenesis. Journal of Proteome Research 2018, 17 (9) , 3143-3152.
    3. Sarah-Marie Saatori, Tanner J. Perez, and Steven M. Graham . Variable-Temperature NMR Spectroscopy, Conformational Analysis, and Thermodynamic Parameters of Cyclic Adenosine 5′-Diphosphate Ribose Agonists and Antagonists. The Journal of Organic Chemistry 2018, 83 (5) , 2554-2569.
    4. Qi Ding, Ke Wen, Qian Li, Qi-Hang Zhao, Jia-Le Zhao, Yun-Fei Xiao, Xiao-Hui Guan, Mei-Xiu Jiang, Feng Zhang, Ling-Fang Wang. CD38 deficiency promotes skeletal muscle and brown adipose tissue energy expenditure through activating NAD + -Sirt1-PGC1α signaling pathway. Canadian Journal of Physiology and Pharmacology 2023,
    5. Ruoxi Zhao, Shigang Zheng, Ying Li, Xueqin Zhang, Dan Rao, Ze Chun, Yadong Hu. As a novel anticancer candidate, ether extract of Dendrobium nobile overstimulates cellular protein biosynthesis to induce cell stress and autophagy. Journal of Applied Biomedicine 2023, 21 (1) , 23-35.
    6. Munehiro Kitada, Shin-ichi Araki, Daisuke Koya. The Role of CD38 in the Pathogenesis of Cardiorenal Metabolic Disease and Aging, an Approach from Basic Research. Cells 2023, 12 (4) , 595.
    7. Yingying Ma, Meiqi Yi, Weixuan Wang, Xiaohui Liu, Qingtao Wang, Chongdong Liu, Yuling Chen, Haiteng Deng. Oxidative degradation of dihydrofolate reductase increases CD38-mediated ferroptosis susceptibility. Cell Death & Disease 2022, 13 (11)
    8. Angelique Cercillieux, Eleonora Ciarlo, Carles Canto. Balancing NAD+ deficits with nicotinamide riboside: therapeutic possibilities and limitations. Cellular and Molecular Life Sciences 2022, 79 (8)
    9. Songbiao Zhu, Wenxi Ding, Yuling Chen, Weixuan Wang, Renhua Xu, Chongdong Liu, Xiaohui Liu, Haiteng Deng. High VHL Expression Reverses Warburg Phenotype and Enhances Immunogenicity in Kidney Tumor Cells. Genomics, Proteomics & Bioinformatics 2022, 20 (4) , 657-669.
    10. Sainiteesh Maddineni, John L Silberstein, John B Sunwoo. Emerging NK cell therapies for cancer and the promise of next generation engineering of iPSC-derived NK cells. Journal for ImmunoTherapy of Cancer 2022, 10 (5) , e004693.
    11. Xinshi Wang, Hai-Jun He, Xi Xiong, Shuoting Zhou, Wen-Wen Wang, Liang Feng, Ruiyu Han, Cheng-Long Xie. NAD+ in Alzheimer’s Disease: Molecular Mechanisms and Systematic Therapeutic Evidence Obtained in vivo. Frontiers in Cell and Developmental Biology 2021, 9
    12. Patrycja Jablonska, Barbara Kutryb‐Zajac, Paulina Mierzejewska, Agnieszka Jasztal, Barbara Bocian, Romuald Lango, Jan Rogowski, Stefan Chlopicki, Ryszard T. Smolenski, Ewa M. Slominska. The new insight into extracellular NAD + degradation‐the contribution of CD38 and CD73 in calcific aortic valve disease. Journal of Cellular and Molecular Medicine 2021, 25 (13) , 5884-5898.
    13. Bledi Petriti, Pete A. Williams, Gerassimos Lascaratos, Kai-Yin Chau, David F. Garway-Heath. Neuroprotection in Glaucoma: NAD+/NADH Redox State as a Potential Biomarker and Therapeutic Target. Cells 2021, 10 (6) , 1402.
    14. Meisam Naeimi Kararoudi, Yuya Nagai, Ezgi Elmas, Marcelo de Souza Fernandes Pereira, Syed Abbas Ali, Philip Hollingsworth Imus, Darren Wethington, Ivan Marques Borrello, Dean Anthony Lee, Gabriel Ghiaur. CD38 deletion of human primary NK cells eliminates daratumumab-induced fratricide and boosts their effector activity. Blood 2020, 136 (21) , 2416-2427.
    15. John WR Kincaid, Nathan A Berger. NAD metabolism in aging and cancer. Experimental Biology and Medicine 2020, 245 (17) , 1594-1614.
    16. Dan Xing, Wei Liu, Jiao Jiao Li, Longwei Liu, Anqi Guo, Bin Wang, Hongsheng Yu, Yu Zhao, Yuling Chen, Zhifeng You, Cheng Lyu, Wenjing Li, Aifeng Liu, Yanan Du, Jianhao Lin. Engineering 3D functional tissue constructs using self-assembling cell-laden microniches. Acta Biomaterialia 2020, 114 , 170-182.
    17. Anwesha Kar, Shikhar Mehrotra, Shilpak Chatterjee. CD38: T Cell Immuno-Metabolic Modulator. Cells 2020, 9 (7) , 1716.
    18. Pamlea N. Brady, Anupam Goel, Margaret A. Johnson. Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity. Microbiology and Molecular Biology Reviews 2019, 83 (1)
    19. Huei-Yu Chen, Atikul Islam, Tien-Ming Yuan, Shi-Wen Chen, Pei-Fen Liu, Pin Ju Chueh. Regulation of tNOX expression through the ROS-p53-POU3F2 axis contributes to cellular responses against oxaliplatin in human colon cancer cells. Journal of Experimental & Clinical Cancer Research 2018, 37 (1)
    20. Jack Mottahedeh, Michael C. Haffner, Tristan R. Grogan, Takao Hashimoto, Preston D. Crowell, Himisha Beltran, Andrea Sboner, Rohan Bareja, David Esopi, William B. Isaacs, Srinivasan Yegnasubramanian, Matthew B. Rettig, David A. Elashoff, Elizabeth A. Platz, Angelo M. De Marzo, Michael A. Teitell, Andrew S. Goldstein. CD38 is methylated in prostate cancer and regulates extracellular NAD+. Cancer & Metabolism 2018, 6 (1)
    21. Weixuan Wang, Yadong Hu, Changmei Yang, Songbiao Zhu, Xiaofei Wang, Zhenyu Zhang, Haiteng Deng. Decreased NAD Activates STAT3 and Integrin Pathways to Drive Epithelial-Mesenchymal Transition. Molecular & Cellular Proteomics 2018, 17 (10) , 2005-2017.
    22. Eduardo N. Chini, Claudia C.S. Chini, Jair Machado Espindola Netto, Guilherme C. de Oliveira, Wim van Schooten. The Pharmacology of CD38/NADase: An Emerging Target in Cancer and Diseases of Aging. Trends in Pharmacological Sciences 2018, 39 (4) , 424-436.
    23. Weixuan Wang, Yadong Hu, Xiaofei Wang, Qingtao Wang, Haiteng Deng. ROS-Mediated 15-Hydroxyprostaglandin Dehydrogenase Degradation via Cysteine Oxidation Promotes NAD+-Mediated Epithelial-Mesenchymal Transition. Cell Chemical Biology 2018, 25 (3) , 255-261.e4.
    24. S Takao, W Chien, V Madan, D-C Lin, L-W Ding, Q-Y Sun, A Mayakonda, M Sudo, L Xu, Y Chen, Y-Y Jiang, S Gery, M Lill, E Park, W Senapedis, E Baloglu, M Müschen, H P Koeffler. Targeting the vulnerability to NAD+ depletion in B-cell acute lymphoblastic leukemia. Leukemia 2018, 32 (3) , 616-625.
    25. Qingwei Ruan, Jian Ruan, Weibin Zhang, Feng Qian, Zhuowei Yu. Targeting NAD + degradation: The therapeutic potential of flavonoids for Alzheimer's disease and cognitive frailty. Pharmacological Research 2018, 128 , 345-358.
    26. Wusheng Xiao, Rui-Sheng Wang, Diane E. Handy, Joseph Loscalzo. NAD(H) and NADP(H) Redox Couples and Cellular Energy Metabolism. Antioxidants & Redox Signaling 2018, 28 (3) , 251-272.
    27. Elena Katsyuba, Johan Auwerx. NAD + Modulation. 2018, 27-44.
    28. Rosemary A Fricker, Emma L Green, Stuart I Jenkins, Síle M Griffin. The Influence of Nicotinamide on Health and Disease in the Central Nervous System. International Journal of Tryptophan Research 2018, 11 , 117864691877665.
    29. Claudia C.S. Chini, Mariana G. Tarragó, Eduardo N. Chini. NAD and the aging process: Role in life, death and everything in between. Molecular and Cellular Endocrinology 2017, 455 , 62-74.
    30. G. Sultani, A. F. Samsudeen, B. Osborne, N. Turner. NAD + : A key metabolic regulator with great therapeutic potential. Journal of Neuroendocrinology 2017, 29 (10)
    31. Elena Katsyuba, Johan Auwerx. Modulating NAD + metabolism, from bench to bedside. The EMBO Journal 2017, 36 (18) , 2670-2683.
    32. Terence A. McGonigle, Kevin N. Keane, Simon Ghaly, Kim W. Carter, Denise Anderson, Naomi M. Scott, Helen S. Goodridge, Amy Dwyer, Eloise Greenland, Fiona J. Pixley, Philip Newsholme, Prue H. Hart. UV Irradiation of Skin Enhances Glycolytic Flux and Reduces Migration Capabilities in Bone Marrow–Differentiated Dendritic Cells. The American Journal of Pathology 2017, 187 (9) , 2046-2059.
    33. Xu Jiang, Xiaoyong Jiang, Yun Feng, Renhua Xu, Qingtao Wang, Haiteng Deng, . Proteomic Analysis of eIF5B Silencing-Modulated Proteostasis. PLOS ONE 2016, 11 (12) , e0168387.
    34. Eric Verdin. NAD + in aging, metabolism, and neurodegeneration. Science 2015, 350 (6265) , 1208-1213.
    35. Silverio Ruggieri, Giuseppe Orsomando, Leonardo Sorci, Nadia Raffaelli. Regulation of NAD biosynthetic enzymes modulates NAD-sensing processes to shape mammalian cell physiology under varying biological cues. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 2015, 1854 (9) , 1138-1149.
    36. Carles Cantó, Keir J. Menzies, Johan Auwerx. NAD+ Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus. Cell Metabolism 2015, 22 (1) , 31-53.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Your Mendeley pairing has expired. Please reconnect