CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels

Chini, Claudia C.S.; Peclat, Thais; Warner, Gina M.; Kashyap, Sonu; Espindola-Netto, Jair M.; Oliveira, Guilherme C. de; Gomez, Lilian Sales; Hogan, Kelly A.; Tarragó, Mariana G.; Puranik, Amrutesh S.; Agorrody, Guillermo; Thompson, Katie L.; Dang, Kevin; Clarke, Starlynn; Childs, Bennett G.; Kanamori, Karina S.; Witte, Micaela A.; Vidal, Paola; Kirkland, Anna L.; Cecco, Marco De; Chellappa, Karthikeyani; McReynolds, Melanie R.; Jankowski, Connor S.R.; Tchkonia, Tamara; Kirkland, James L.; Sedivy, John M.; Deursen, Jan M. van; Baker, Darren J.; Schooten, Wim van; Rabinowitz, Joshua D.; Baur, Joseph A.; Chini, Eduardo N.

doi:10.1038/s42255-020-00298-z

Cited by 217 publications

(227 citation statements)

References 82 publications

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“…Researches have proved that the elevation of CD38 expression plays an inverse role in the regulation of nicotinamide adenine dinucleotide (NAD + ) and maintenance of NAD + homeostasis is critical for maintaining the normal function of the immune cells, such as cytotoxic (CD8+) T cells and macrophages [ 7 , 8 ]. CD38 possesses NAD + glycohydrolase activity and ADP ribosyl cyclase activity, both of which could convert NAD + to cADPR as well as hydrolase activity that converted cADPR to ADPR [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

The intrinsic role and mechanism of tumor expressed-CD38 on lung adenocarcinoma progression

Gao

Liu

et al. 2021

Cell Death Dis

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It has been recently reported that CD38 expressed on tumor cells of multiple murine and human origins could be upregulated in response to PD-L1 antibody therapy, which led to dysfunction of tumor-infiltrating CD8+ T immune cells due to increasing the production of adenosine. However, the role of tumor expressed-CD38 on neoplastic formation and progression remains elusive. In the present study, we aimed to delineate the molecular and biochemical function of the tumor-associated CD38 in lung adenocarcinoma progression. Our clinical data showed that the upregulation of tumor-originated CD38 was correlated with poor survival of lung cancer patients. Using multiple in vitro assays we found that the enzymatic activity of tumor expressed-CD38 facilitated lung cancer cell migration, proliferation, colony formation, and tumor development. Consistently, our in vivo results showed that inhibition of the enzymatic activity or antagonizing the enzymatic product of CD38 resulted in the similar inhibition of tumor proliferation and metastasis as CD38 gene knock-out or mutation. At biochemical level, we further identified that cADPR, the mainly hydrolytic product of CD38, was responsible for inducing the opening of TRPM2 iron channel leading to the influx of intracellular Ca2+ and then led to increasing levels of NRF2 while decreasing expression of KEAP1 in lung cancer cells. These findings suggested that malignant lung cancer cells were capable of using cADPR catalyzed by CD38 to facilitate tumor progression, and blocking the enzymatic activity of CD38 could be represented as an important strategy for preventing tumor progression.

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Section: Introductionmentioning

confidence: 99%

The intrinsic role and mechanism of tumor expressed-CD38 on lung adenocarcinoma progression

Gao

Liu

et al. 2021

Cell Death Dis

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“…The SASP factors secreted from senescent cells such as senescent ECs can increase the expression of CD38 in non-senescent cells in vitro ( Chini et al, 2019 ). Recently, studies from two independent groups ( Chini et al, 2020 ; Covarrubias et al, 2020 ) revealed that CD38+ proinflammatory macrophages are the major cells that cause the decline of NAD+ levels in white adipose tissue and liver of mice. The expression of CD38 is induced in the proinflammatory macrophages through the SASP factors of senescent cells in vivo .…”

Section: Recent Advances In Cellular Senescencementioning

confidence: 99%

Vascular Endothelial Senescence: Pathobiological Insights, Emerging Long Noncoding RNA Targets, Challenges and Therapeutic Opportunities

Sun

Feinberg

2021

Front. Physiol.

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Cellular senescence is a stable form of cell cycle arrest in response to various stressors. While it serves as an endogenous pro-resolving mechanism, detrimental effects ensue when it is dysregulated. In this review, we introduce recent advances for cellular senescence and inflammaging, the underlying mechanisms for the reduction of nicotinamide adenine dinucleotide in tissues during aging, new knowledge learned from p16 reporter mice, and the development of machine learning algorithms in cellular senescence. We focus on pathobiological insights underlying cellular senescence of the vascular endothelium, a critical interface between blood and all tissues. Common causes and hallmarks of endothelial senescence are highlighted as well as recent advances in endothelial senescence. The regulation of cellular senescence involves multiple mechanistic layers involving chromatin, DNA, RNA, and protein levels. New targets are discussed including the roles of long noncoding RNAs in regulating endothelial cellular senescence. Emerging small molecules are highlighted that have anti-aging or anti-senescence effects in age-related diseases and impact homeostatic control of the vascular endothelium. Lastly, challenges and future directions are discussed including heterogeneity of endothelial cells and endothelial senescence, senescent markers and detection of senescent endothelial cells, evolutionary differences for immune surveillance in mice and humans, and long noncoding RNAs as therapeutic targets in attenuating cellular senescence. Accumulating studies indicate that cellular senescence is reversible. A better understanding of endothelial cellular senescence through lifestyle and pharmacological interventions holds promise to foster a new frontier in the management of cardiovascular disease risk.

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“…Recent studies showed that inflammation increases CD38-mediated NAD + degradation activity, which decreases NAD + . The increase in CD38 in metabolic tissues during aging is likely mediated by accumulation of pro-inflammatory M1-like macrophages that also express CD38 ( Chini et al, 2020 ; Covarrubias et al, 2020 ).…”

Section: Immunity Kyn Pathway Metabolites and De Novo Nad + Metabolismmentioning

confidence: 99%

“…Consequently, NAD + has a multifarious and highly important influence on cellular health, affecting an extensive suite of processes, including: DNA repair, central metabolism, circadian rhythms, meiosis and lifespan ( Imai and Guarente, 2014 ; Kato and Lin, 2014 ; Nikiforov et al, 2015 ; Chini et al, 2016 ; Yoshino et al, 2018 ; Okabe et al, 2019 ; Castro-Portuguez and Sutphin, 2020 ). Owing to its centrality in cellular homeostasis, defects in NAD + metabolism are often associated with a variety of disease states, seen in diabetes, neurological disorders, and various cancers ( Schwarcz et al, 2012 ; Imai and Guarente, 2014 ; Cantó et al, 2015 ; Garten et al, 2015 ; Nikiforov et al, 2015 ; Verdin, 2015 ; Cheng et al, 2016 ; Chini et al, 2016 ; Yang and Sauve, 2016 ; Williams et al, 2017 ; Liu et al, 2018 ; Poyan Mehr et al, 2018 ; Yaku et al, 2018 ; Yoshino et al, 2018 ; Okabe et al, 2019 ; Chini et al, 2020 ; Covarrubias et al, 2020 ; Katsyuba et al, 2020 ; Covarrubias et al, 2021 ). Administration of NAD + precursors such as nicotinamide mononucleotide (NMN), nicotinamide (NAM), nicotinic acid riboside (NaR), nicotinamide riboside (NR), and dihydronicotinamide riboside (NRH) has been shown to increase NAD + levels and ameliorate associated deficiencies in various model systems and in humans ( Belenky et al, 2007 ; Brown et al, 2014 ; Cantó et al, 2015 ; Edwards et al, 2015 ; Garten et al, 2015 ; Verdin, 2015 ; Chini et al, 2016 ; Lin et al, 2016 ; Ryu et al, 2016 ; Yang and Sauve, 2016 ; Zhang et al, 2016 ; Williams et al, 2017 ; Katsyuba et al, 2018 ; Liu et al, 2018 ; Meng et al, 2018 ; Mitchell et al, 2018 ; Poyan Mehr et al, 2018 ; Rajman et al, 2018 ; Yoshino et al, 2018 ; Sambeat et al, 2019 ; Vannini et al, 2019 ; ...…”

Section: Introductionmentioning

confidence: 99%

NAD+ Metabolism, Metabolic Stress, and Infection

Groth

Venkatakrishnan

Lin

2021

Front. Mol. Biosci.

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Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite with wide-ranging and significant roles in the cell. Defects in NAD+ metabolism have been associated with many human disorders; it is therefore an emerging therapeutic target. Moreover, NAD+ metabolism is perturbed during colonization by a variety of pathogens, either due to the molecular mechanisms employed by these infectious agents or by the host immune response they trigger. Three main biosynthetic pathways, including the de novo and salvage pathways, contribute to the production of NAD+ with a high degree of conservation from bacteria to humans. De novo biosynthesis, which begins with l-tryptophan in eukaryotes, is also known as the kynurenine pathway. Intermediates of this pathway have various beneficial and deleterious effects on cellular health in different contexts. For example, dysregulation of this pathway is linked to neurotoxicity and oxidative stress. Activation of the de novo pathway is also implicated in various infections and inflammatory signaling. Given the dynamic flexibility and multiple roles of NAD+ intermediates, it is important to understand the interconnections and cross-regulations of NAD+ precursors and associated signaling pathways to understand how cells regulate NAD+ homeostasis in response to various growth conditions. Although regulation of NAD+ homeostasis remains incompletely understood, studies in the genetically tractable budding yeast Saccharomyces cerevisiae may help provide some molecular basis for how NAD+ homeostasis factors contribute to the maintenance and regulation of cellular function and how they are regulated by various nutritional and stress signals. Here we present a brief overview of recent insights and discoveries made with respect to the relationship between NAD+ metabolism and selected human disorders and infections, with a particular focus on the de novo pathway. We also discuss how studies in budding yeast may help elucidate the regulation of NAD+ homeostasis.

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CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels

Cited by 217 publications

References 82 publications

The intrinsic role and mechanism of tumor expressed-CD38 on lung adenocarcinoma progression

The intrinsic role and mechanism of tumor expressed-CD38 on lung adenocarcinoma progression

Vascular Endothelial Senescence: Pathobiological Insights, Emerging Long Noncoding RNA Targets, Challenges and Therapeutic Opportunities

NAD+ Metabolism, Metabolic Stress, and Infection

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