SIRT2 inhibition by AGK2 enhances mycobacteria-specific stem cell memory responses by modulating beta-catenin and glycolysis

Bhaskar, Ashima; Pahuja, Isha; Negi, Kriti; Verma, Akansksha; Ghoshal, Antara; Mathew, Babu; Tripathi, Gaurav; Maras, Jaswinder Singh; Chaturvedi, Shivam; Dwivedi, Ved Prakash

doi:10.1016/j.isci.2023.106644

Cited by 10 publications

(2 citation statements)

References 59 publications

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“…For instance, Biapenem was shown to modulate p38 signaling in host macrophages while Withaferin-A and Berberine induced STAT pathway and NOTCH-Akt axis, respectively, in the T cells to induce host protective memory immune responses ( 29 , 32 , 34 ). We have also shown that the integration of host-targeted inhibitors such as AGK2 (SIRT2 inhibitor) constrains intracellular growth of M. tuberculosis and also improves vaccine efficacy by influencing host immunity ( 45 , 46 ).…”

Section: Discussionmentioning

confidence: 99%

Immunoinhibitory effects of anti-tuberculosis therapy induce the host vulnerability to tuberculosis recurrence

Pahuja,

Ghoshal,

Okieh

et al. 2024

Microbiol Spectr

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The host immune responses play a pivotal role in the establishment of long-term memory responses, which effectively aids in infection clearance. However, the prevailing anti-tuberculosis therapy, while aiming to combat tuberculosis (TB), also debilitates innate and adaptive immune components of the host. In this study, we explored how the front-line anti-TB drugs impact the host immune cells by modulating multiple signaling pathways and subsequently leading to disease relapse. Administration of these drugs led to a reduction in innate immune activation and also the cytokines required to trigger protective T cell responses. Moreover, these drugs led to activation-induced cell death in the mycobacterial-specific T cell leading to a reduced killing capacity. Furthermore, these drugs stalled the T cell differentiation into memory subsets by modulating the activation of STAT3, STAT4, FOXO1, and NFκB transcription factors and hampering the Th1 and Th17-mediated long-term host protective memory responses. These findings suggest the urgent need to augment directly observed treatment, short-course (DOTS) therapy with immunomodulatory agents to mitigate the adverse effects linked to the treatment. IMPORTANCE As a central component of TB eradication initiatives, directly observed treatment, short-course (DOTS) therapy imparts immune-dampening effects during the course of treatment. This approach undermines the host immune system by delaying the activation process and lowering the immune response. In our investigation, we have unveiled the impact of DOTS on specific immune cell populations. Notably, the signaling pathways involving STAT3 and STAT4 critical for memory responses and NFκβ associated with pro-inflammation were substantially declined due to the therapy. Consequently, these drugs exhibit limited effectiveness in preventing recurrence of the disease. These observations highlight the imperative integration of immunomodulators to manage TB infection.

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Section: Discussionmentioning

confidence: 99%

Immunoinhibitory effects of anti-tuberculosis therapy induce the host vulnerability to tuberculosis recurrence

Pahuja,

Ghoshal,

Okieh

et al. 2024

Microbiol Spectr

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“…Oxidative phosphorylation (OXPHOS) and glycolysis are the two critical energy metabolic pathways in mammalian cells [6][7][8][9][10] . OXPHOS is mainly through the cellular mitochondrial respiratory chain complex way to synthesize large amounts of ATP for meeting the daily needs of the cells [11][12][13] .…”

Section: Introductionmentioning

confidence: 99%

CST1 promotes the metastasis by mediating an oxidative phosphorylation/MEK/ERK axis in esophageal squamous carcinoma cancer

Zhang

Chen

Wang

et al. 2023

Preprint

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Cysteine Protease Inhibitor 1 (CST1), a cystatin superfamily protein with the effect on the inhibition of cysteine protease activity , is reported to be involved in the development of many malignancies. Mitochondrial oxidative phosphorylation (OXPHOS) also plays an important role on regulating cancer cell growth. However, the relationship and role of CST1 and OXPHOS on esophageal squamous cell carcinoma (ESCC) remains unknown. In our pilot study, CST1 was shown the potential of promoting ESCC migration and invasion by the activation of MEK/ERK pathway. Especially mentioned, we found that CST1 is closely associated with OXPHOS by the analysis of transcriptome sequencing. And then, based on real-time ATP rate assay, mitochondrial complex I enzyme activity assay, immunofluorescence (IF), co-immunoprecipitation (CO-IP), and additions of OXPHOS inhibitor Rotenone and MEK/ERK inhibitor PD98059, we defined the effect of CST1 on mitochondrial complex I enzyme activity by interacting with GRIM19 protein to elevate OXPHOS levels, and the reciprocal regulatory relationship existed between OXPHOS and MEK/ERK pathway in ESCC cells. Finally, a study in vivo well demonstrated the potential of CST1 on ESCC metastasis by the regulation of OXPHOS and MEK/ERK pathway. This study is the first to unveil the oncogenic role of CST1 on ESCC development by enhancing mitochondrial respiratory chain complex I activity to activate an OXPHOS/MEK/ERK axis, and then promote ESCC metastasis, suggesting that CST1/OXPHOS might be a promising target for ESCC treatment.

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Fisetin disrupts mitochondrial homeostasis via superoxide dismutase 2 acetylation in pancreatic adenocarcinoma

Ding,

Xie,

et al. 2024

Phytotherapy Research

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Pancreatic adenocarcinoma (PDAC) is one of the most lethal malignant tumors with an urgent need for precision medicine strategies. The present study seeks to assess the antitumor effects of fisetin, and characterize its impact on PDAC. Multi‐omic approaches include proteomic, transcriptomic, and metabolomic analyses. Further validation includes the assessment of mitochondria‐derived reactive oxygen species (mtROS), mitochondrial membrane potential, as well as ATP generation. Molecular docking, immunoprecipitation, and proximity ligation assay were used to detect the interactions among fiseitn, superoxide dismutase 2 (SOD2), and sirtuin 2 (SIRT2). We showed that fisetin disrupted mitochondrial homeostasis and induced SOD2 acetylation in PDAC. Further, we produced site mutants to determine that fisetin‐induced mtROS were dependent on SOD2 acetylation. Fisetin inhibited SIRT2 expression, thus blocking SOD2 deacetylation. SIRT2 overexpression could impede fisetin‐induced SOD2 acetylation. Additionally, untargeted metabolomic analysis revealed an acceleration of folate metabolism with fisetin. Collectively, our findings suggest that fisetin disrupts mitochondrial homeostasis, eliciting an important cancer‐suppressive role; thus, fisetin may serve as a promising therapeutic for PDAC.

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SIRT2 inhibition by AGK2 enhances mycobacteria-specific stem cell memory responses by modulating beta-catenin and glycolysis

Cited by 10 publications

References 59 publications

Immunoinhibitory effects of anti-tuberculosis therapy induce the host vulnerability to tuberculosis recurrence

Immunoinhibitory effects of anti-tuberculosis therapy induce the host vulnerability to tuberculosis recurrence

CST1 promotes the metastasis by mediating an oxidative phosphorylation/MEK/ERK axis in esophageal squamous carcinoma cancer

Fisetin disrupts mitochondrial homeostasis via superoxide dismutase 2 acetylation in pancreatic adenocarcinoma

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