SIRT1: A Potential Therapeutic Target in Autoimmune Diseases

The morbidity and mortality of autoimmune diseases (Ads) have been increasing worldwide, and the identification of novel therapeutic strategies for prevention and treatment is urgently needed. Sirtuin 1 (SIRT1), a member of the class III family of nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases, has been reported to participate in the progression of several diseases. SIRT1 also regulates inflammation, oxidative stress, mitochondrial function, immune responses, cellular differentiation, proliferation and metabolism, and its altered functions are likely involved in Ads. Several inhibitors and activators have been shown to affect the development of Ads. SIRT1 may represent a novel therapeutic target in these diseases, and small molecules or natural products that modulate the functions of SIRT1 are potential therapeutic agents. In the present review, we summarize current studies of the biological functions of SIRT1 and its role in the pathogenesis and treatment of Ads.

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The SARS-CoV-2 conserved macrodomain is a mono-ADP-ribosylhydrolase

10.1101/2020.05.11.089375 ◽

2020 ◽

Cited By ~ 6

Author(s):

Yousef M.O. Alhammad ◽

Maithri M. Kashipathy ◽

Anuradha Roy ◽

Jean-Philippe Gagné ◽

Peter McDonald ◽

...

Keyword(s):

Crystal Structure ◽

Therapeutic Target ◽

Viral Infections ◽

Protein Domain ◽

Structural Protein ◽

Potential Therapeutic Target ◽

Novel Therapeutic Strategies ◽

Design And Testing ◽

Translational Process ◽

Novel Therapeutic

ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other SARS-like-CoVs encode 3 tandem macrodomains within non-structural protein 3 (nsp3). The first macrodomain, Mac1, is conserved throughout CoVs, and binds to and hydrolyzes mono-ADP-ribose (MAR) from target proteins. Mac1 likely counters host-mediated anti-viral ADP-ribosylation, a posttranslational modification that is part of the host response to viral infections. Mac1 is essential for pathogenesis in multiple animal models of CoV infection, implicating it as a virulence factor and potential therapeutic target. Here we report the crystal structure of SARS-CoV-2 Mac1 in complex with ADP-ribose. SARS-CoV-2, SARS-CoV and MERS-CoV Mac1 exhibit similar structural folds and all 3 proteins bound to ADP-ribose with low μM affinities. Importantly, using ADP-ribose detecting binding reagents in both a gel-based assay and novel ELISA assays, we demonstrated de-MARylating activity for all 3 CoV Mac1 proteins, with the SARS-CoV-2 Mac1 protein leading to a more rapid loss of substrate compared to the others. In addition, none of these enzymes could hydrolyze poly-ADP-ribose. We conclude that the SARS-CoV-2 and other CoV Mac1 proteins are MAR-hydrolases with similar functions, indicating that compounds targeting CoV Mac1 proteins may have broad anti-CoV activity.IMPORTANCESARS-CoV-2 has recently emerged into the human population and has led to a worldwide pandemic of COVID-19 that has caused greater than 900 thousand deaths worldwide. With, no currently approved treatments, novel therapeutic strategies are desperately needed. All coronaviruses encode for a highly conserved macrodomain (Mac1) that binds to and removes ADP-ribose adducts from proteins in a dynamic post-translational process increasingly recognized as an important factor that regulates viral infection. The macrodomain is essential for CoV pathogenesis and may be a novel therapeutic target. Thus, understanding its biochemistry and enzyme activity are critical first steps for these efforts. Here we report the crystal structure of SARS-CoV-2 Mac1 in complex with ADP-ribose, and describe its ADP-ribose binding and hydrolysis activities in direct comparison to SARS-CoV and MERS-CoV Mac1 proteins. These results are an important first step for the design and testing of potential therapies targeting this unique protein domain.

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The SARS-CoV-2 conserved macrodomain is a mono-ADP-ribosylhydrolase

Journal of Virology ◽

10.1128/jvi.01969-20 ◽

2020 ◽

Cited By ~ 1

Author(s):

Yousef M.O. Alhammad ◽

Maithri M. Kashipathy ◽

Anuradha Roy ◽

Jean-Philippe Gagné ◽

Peter McDonald ◽

...

Keyword(s):

Crystal Structure ◽

Therapeutic Target ◽

Viral Infections ◽

Protein Domain ◽

Structural Protein ◽

Potential Therapeutic Target ◽

Novel Therapeutic Strategies ◽

Design And Testing ◽

Translational Process ◽

Novel Therapeutic

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other SARS-related CoVs encode 3 tandem macrodomains within non-structural protein 3 (nsp3). The first macrodomain, Mac1, is conserved throughout CoVs, and binds to and hydrolyzes mono-ADP-ribose (MAR) from target proteins. Mac1 likely counters host-mediated anti-viral ADP-ribosylation, a posttranslational modification that is part of the host response to viral infections. Mac1 is essential for pathogenesis in multiple animal models of CoV infection, implicating it as a virulence factor and potential therapeutic target. Here we report the crystal structure of SARS-CoV-2 Mac1 in complex with ADP-ribose. SARS-CoV-2, SARS-CoV and MERS-CoV Mac1 exhibit similar structural folds and all 3 proteins bound to ADP-ribose with low μM affinities. Importantly, using ADP-ribose detecting binding reagents in both a gel-based assay and novel ELISA assays, we demonstrated de-MARylating activity for all 3 CoV Mac1 proteins, with the SARS-CoV-2 Mac1 protein leading to a more rapid loss of substrate compared to the others. In addition, none of these enzymes could hydrolyze poly-ADP-ribose. We conclude that the SARS-CoV-2 and other CoV Mac1 proteins are MAR-hydrolases with similar functions, indicating that compounds targeting CoV Mac1 proteins may have broad anti-CoV activity. IMPORTANCE SARS-CoV-2 has recently emerged into the human population and has led to a worldwide pandemic of COVID-19 that has caused greater than 1.2 million deaths worldwide. With, no currently approved treatments, novel therapeutic strategies are desperately needed. All coronaviruses encode for a highly conserved macrodomain (Mac1) that binds to and removes ADP-ribose adducts from proteins in a dynamic post-translational process increasingly recognized as an important factor that regulates viral infection. The macrodomain is essential for CoV pathogenesis and may be a novel therapeutic target. Thus, understanding its biochemistry and enzyme activity are critical first steps for these efforts. Here we report the crystal structure of SARS-CoV-2 Mac1 in complex with ADP-ribose, and describe its ADP-ribose binding and hydrolysis activities in direct comparison to SARS-CoV and MERS-CoV Mac1 proteins. These results are an important first step for the design and testing of potential therapies targeting this unique protein domain.

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MiR-29a: a potential therapeutic target and promising biomarker in tumors

Bioscience Reports ◽

10.1042/bsr20171265 ◽

2018 ◽

Vol 38 (1) ◽

Cited By ~ 10

Author(s):

Jin-yan Wang ◽

Qian Zhang ◽

Dan-dan Wang ◽

Wei Yan ◽

Huan-huan Sha ◽

...

Keyword(s):

Cell Proliferation ◽

Therapeutic Target ◽

Therapeutic Strategy ◽

Transcriptional Level ◽

Additional Insight ◽

Potential Therapeutic Target ◽

Rna Molecules ◽

Non Coding Rna ◽

Non Coding Rnas ◽

Novel Therapeutic

MiRNAs, small non-coding RNA molecules, were recognized to be associated with the incidence and development of diverse neoplasms. MiRNAs were small non-coding RNAs that could regulate post-transcriptional level by binding to 3′-UTR of target mRNAs. Amongst which, miR-29a was demonstrated that it had significant impact on oncogenicity in various neoplasms through binding to critical genes which enhanced or inhibited the progression of cancers. MiR-29a participated in kinds of physiological and pathological processes, including virus replication, cell proliferation, differentiation, apoptosis, fibrosis, angiogenesis, tumorigenicity, metastasis, drug-resistance, and so on. According to its sufficient sensitivity and specificity, many studies showed that miR-29a might serve as a potential therapeutic target and promising biomarker in various tumors. In this review, we discussed the functions of miR-29a and its potential application in the diagnosis, treatment and stages of carcinoma, which could provide additional insight to develop a novel therapeutic strategy.

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The promise of mTOR as a therapeutic target pathway in idiopathic pulmonary fibrosis

European Respiratory Review ◽

10.1183/16000617.0269-2020 ◽

2020 ◽

Vol 29 (157) ◽

pp. 200269

Author(s):

Manuela Platé ◽

Delphine Guillotin ◽

Rachel C Chambers

Keyword(s):

Extracellular Matrix ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Therapeutic Target ◽

Critical Role ◽

Mammalian Target Of Rapamycin ◽

Lung Parenchyma ◽

Extracellular Signals ◽

Novel Therapeutic Strategies ◽

Novel Therapeutic

Idiopathic pulmonary fibrosis (IPF) is characterised by the progressive deposition of excessive extracellular matrix proteins within the lung parenchyma and represents the most rapidly progressive and fatal of all fibrotic conditions. Current anti-fibrotic drugs approved for the treatment of IPF fail to halt disease progression and have significant side-effect profiles. Therefore, there remains a pressing need to develop novel therapeutic strategies for IPF. Mammalian target of rapamycin (mTOR) forms the catalytic subunit of two complexes, mTORC1 and mTORC2. mTORC1 acts as critical cellular sensor which integrates intracellular and extracellular signals to reciprocally regulate a variety of anabolic and catabolic processes. The emerging evidence for a critical role for mTORC1 in influencing extracellular matrix production, metabolism, autophagy and senescence in the setting of IPF highlights this axis as a novel therapeutic target with the potential to impact multiple IPF pathomechanisms.

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Insulin-Like Growth Factor-I Regulation of Immune Function: A Potential Therapeutic Target in Autoimmune Diseases?

Pharmacological Reviews ◽

10.1124/pr.109.002469 ◽

2010 ◽

Vol 62 (2) ◽

pp. 199-236 ◽

Cited By ~ 119

Author(s):

Terry J. Smith

Keyword(s):

Growth Factor ◽

Autoimmune Diseases ◽

Immune Function ◽

Therapeutic Target ◽

Insulin Like Growth Factor ◽

Potential Therapeutic Target ◽

Factor I ◽

Growth Factor I

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Activation of c-Jun N-Terminal Kinase, a Potential Therapeutic Target in Autoimmune Arthritis

Cells ◽

10.3390/cells9112466 ◽

2020 ◽

Vol 9 (11) ◽

pp. 2466

Author(s):

Benjamin Lai ◽

Chien-Hsiang Wu ◽

Jenn-Haung Lai

Keyword(s):

Immune Responses ◽

Proinflammatory Cytokines ◽

Therapeutic Target ◽

Signaling Molecules ◽

Autoimmune Disorders ◽

Autoimmune Arthritis ◽

Potential Therapeutic Target ◽

Downstream Signaling ◽

Physiological Processes ◽

Complex Manner

The c-Jun-N-terminal kinase (JNK) is a critical mediator involved in various physiological processes, such as immune responses, and the pathogenesis of various diseases, including autoimmune disorders. JNK is one of the crucial downstream signaling molecules of various immune triggers, mainly proinflammatory cytokines, in autoimmune arthritic conditions, mainly including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. The activation of JNK is regulated in a complex manner by upstream kinases and phosphatases. Noticeably, different subtypes of JNKs behave differentially in immune responses. Furthermore, aside from biologics targeting proinflammatory cytokines, small-molecule inhibitors targeting signaling molecules such as Janus kinases can act as very powerful therapeutics in autoimmune arthritis patients unresponsiveness to conventional synthetic antirheumatic drugs. Nevertheless, despite these encouraging therapies, a population of patients with an inadequate therapeutic response to all currently available medications still remains. These findings identify the critical signaling molecule JNK as an attractive target for investigation of the immunopathogenesis of autoimmune disorders and for consideration as a potential therapeutic target for patients with autoimmune arthritis to achieve better disease control. This review provides a useful overview of the roles of JNK, how JNK is regulated in immunopathogenic responses, and the potential of therapeutically targeting JNK in patients with autoimmune arthritis.

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Sirtuin 1 promotes the growth and cisplatin resistance of endometrial carcinoma cells: a novel therapeutic target

Laboratory Investigation ◽

10.1038/labinvest.2015.119 ◽

2015 ◽

Vol 95 (12) ◽

pp. 1363-1373 ◽

Cited By ~ 32

Author(s):

Ryoichi Asaka ◽

Tsutomu Miyamoto ◽

Yasushi Yamada ◽

Hirofumi Ando ◽

David Hamisi Mvunta ◽

...

Keyword(s):

Endometrial Carcinoma ◽

Therapeutic Target ◽

Cisplatin Resistance ◽

Carcinoma Cells ◽

Sirtuin 1 ◽

Novel Therapeutic

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B cell Sirt1 deacetylates histone and non-histone proteins for epigenetic modulation of AID expression and the antibody response

Science Advances ◽

10.1126/sciadv.aay2793 ◽

2020 ◽

Vol 6 (14) ◽

pp. eaay2793 ◽

Cited By ~ 4

Author(s):

Huoqun Gan ◽

Tian Shen ◽

Daniel P. Chupp ◽

Julia R. Taylor ◽

Helia N. Sanchez ◽

...

Keyword(s):

Antibody Response ◽

B Cell ◽

Histone Deacetylases ◽

Somatic Hypermutation ◽

Cytidine Deaminase ◽

Dna Recombination ◽

Sirtuin 1 ◽

B Cell Differentiation ◽

Class Iii ◽

Nonhistone Proteins

Activation-induced cytidine deaminase (AID) mediates immunoglobulin class switch DNA recombination (CSR) and somatic hypermutation (SHM), critical processes for maturation of the antibody response. Epigenetic factors, such as histone deacetylases (HDACs), would underpin B cell differentiation stage–specific AID expression. Here, we showed that NAD+-dependent class III HDAC sirtuin 1 (Sirt1) is highly expressed in resting B cells and down-regulated by stimuli inducing AID. B cell Sirt1 down-regulation, deprivation of NAD+ cofactor, or genetic Sirt1 deletion reduced deacetylation of Aicda promoter histones, Dnmt1, and nuclear factor–κB (NF-κB) p65 and increased AID expression. This promoted class-switched and hypermutated T-dependent and T-independent antibody responses or led to generation of autoantibodies. Genetic Sirt1 overexpression, Sirt1 boost by NAD+, or allosteric Sirt1 enhancement by SRT1720 repressed AID expression and CSR/SHM. By deacetylating histone and nonhistone proteins (Dnmt1 and NF-κB p65), Sirt1 transduces metabolic cues into epigenetic changes to play an important B cell–intrinsic role in modulating antibody and autoantibody responses.

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