Deacetylation of Caveolin-1 by Sirt6 induces autophagy and retards high glucose-stimulated LDL transcytosis and atherosclerosis formation

Zhao, Ying; Xiong, Jun; Yang, Xiaoyan; Bai, Xiangli; Lu, Yajing; Zhu, Lin; Cheng, Wenzhuo; Shao, Meng; Zhu, Yan; Du, Xiaolong; Wang, Li; Yan, Song; Song, Yi; Jin, Si

doi:10.1016/j.metabol.2022.155162

Cited by 41 publications

(32 citation statements)

References 51 publications

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“…Sirtuin 6 (SIRT6) belongs to NAD + -dependent deacetylase, which is widely expressed in mammalian organs, and regulates multiple biological processes, including inflammatory response, oxidative stress, telomere homeostasis, and autophagy [31]. The protective effect of SIRT6 activating autophagy has been proved in different organ injuries, including I/R injury [39][40][41], diabetes [42][43][44][45], and sepsis [19,46,47]. Several studies have recently demonstrated the renal protective effect of SIRT6-induced autophagy in sepsis-induced AKI [47], hypertensive cardiorenal injury [48], podocyte injury [45], and cadmium-induced renal damage [49], respectively.…”

Section: ⁎⁎mentioning

confidence: 99%

Polydatin Attenuates Cisplatin-Induced Acute Kidney Injury via SIRT6-Mediated Autophagy Activation

Zhou

et al. 2022

Oxidative Medicine and Cellular Longevity

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In the treatment of malignant tumors, the effectiveness of cisplatin (CP) is limited by its nephrotoxicity, leading to cisplatininduced acute kidney injury (CP-AKI). Polydatin (PD) has been demonstrated to regulate autophagy in tumors, sepsis, and diabetes. We have recently confirmed that PD attenuated CP-AKI by inhibiting ferroptosis, but it is not clear whether PD can regulate autophagy to protect from CP-AKI. The purpose of this study was to investigate the effect of PD on autophagy in CPtreated HK-2 cells and CP-AKI mouse models, exploring the role of sirtuin 6 (SIRT6) upregulated by PD. In this study, the blocking of autophagy flux was observed in both CP-treated HK-2 cells in vitro and CP-AKI mouse models in vivo, whereas this blocking was reversed by PD, which was characterized by the increase of autophagy microtubule-associated protein light chain 3 II expression and autophagolysosome/autophagosome ratio and the decrease of p62 expression. Furthermore, PD also significantly increased the expression of SIRT6 in vivo and in vitro. The protective effect of PD manifested by the stimulating of autophagy flux, with the reducing of inflammatory response and oxidative stress, which included downregulation of tumor necrosis factor-α and interleukin-1β, decreased activity of myeloperoxidase and content of malondialdehyde, and increased activity of superoxide dismutase and level of glutathione, both in vivo and in vitro, was reversed by either inhibition of autophagy flux by chloroquine or downregulation of SIRT6 by OSS-128167. Taken together, the present findings provide the first evidence demonstrating that PD exhibited nephroprotective effects on CP-AKI by restoring SIRT6-mediated autophagy flux mechanisms.

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Section: ⁎⁎mentioning

confidence: 99%

Polydatin Attenuates Cisplatin-Induced Acute Kidney Injury via SIRT6-Mediated Autophagy Activation

Zhou

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…Thus, Kac plays an essential regulatory role in biological processes. Enhanced histone acetylation has been found in the disease process of GDM and PE [11,12]. Shangguan et al [13] characterized the acetylome profile of placental tissue from PE.…”

Section: Introductionmentioning

confidence: 99%

Integrated proteome and acetylome analyses unveil protein features of gestational diabetes mellitus and preeclampsia

Tang

et al. 2022

Proteomics

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Gestational diabetes mellitus (GDM) and preeclampsia (PE) are associated with maternal and infant health. Although the pathogenesis of PE and GDM remains controversial, oxidative stress is involved in the underlying pathology of GDM and PE. Protein lysine acetylation (Kac) plays an important regulatory role in biological processes. There is little data regarding the association of the maternal acetylome with GDM and PE. This study aimed to assess the potential value of the proteome and acetylome for GDM and PE. In our study, we included placental tissues from healthy individuals (n = 6), GDM patients (n = 6), and PE patients (n = 6) to perform 4D-label free quantification proteomics analysis and PRM analysis. We identified 22 significantly regulated proteins and 192 significantly regulated acetylated proteins between the GDM and PE groups. Furthermore, 192 significantly regulated acetylated proteins were mainly enriched in endoplasmic reticulum stress (ERS) and ferroptosis pathways. Seventeen acetylated sites in these two pathways were verified by PRM analysis. Our comprehensive analysis revealed key features of GDM/PE-significantly regulated acetylated proteins in the placentas from GDM and PE. The results of signaling pathway analysis focused on ERS and ferroptosis. These findings may help

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“…Because protein deacetylation status potentially affect the choice of lysosomal [ 25 ] or proteasomal degradation [ 26 ], we firstly exposed AGS cells to NH 4 Cl (a lysosome inhibitor), 3-MA (an autophagy inhibitor) and MG132 (a proteasome inhibitor) and noticed that NH 4 Cl, but not MG132 (Additional file 1 : Fig. S5A–C), increased the expression of LONP1, suggesting that lysosome is the major organelle responsible for LONP1 turnover.…”

Section: Resultsmentioning

confidence: 99%

Sirt3 restricts tumor initiation via promoting LONP1 deacetylation and K63 ubiquitination

Yan

Sun

et al. 2023

J Transl Med

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Background Sirtuin 3 (Sirt3) is a controversial regulator of carcinogenesis. It residents in the mitochondria and gradually decays during aging. In this study, we tried to investigate the role of Sirt3 in carcinogenesis and to explore its involvement in metabolic alteration. Methods We generated conditional intestinal epithelium Sirt3-knockout mice by crossing ApcMin/+; Villin-Cre with Sirt3fl/fl (AVS) mice. The deacetylation site of Lon protease-1 (LONP1) was identified with Mass spectrometry. The metabolic flux phenotype was determined by Seahorse bioanalyzer. Results We found that intestinal epithelial cell-specific ablation of Sirt3 promotes primary tumor growth via stabilizing mitochondrial LONP1. Notably, we newly identified that Sirt3 deacetylates human oncogene LONP1 at N terminal residue lysine 145 (K145). The LONP1 hyperacetylation-mutant K145Q enhances oxidative phosphorylation to accelerate tumor growth, whereas the deacetylation-mutant K145R produces calorie-restriction like phenotype to restrain tumorigenesis. Sirt3 deacetylates LONP1 at K145 and subsequently facilitates the ESCRT0 complex sorting and K63-ubiquitination that resulted in the degradation of LONP1. Our results sustain the notion that Sirt3 is a tumor-suppressor to maintain the appropriate ubiquitination and degradation of oncogene LONP1. Conclusion Sirt3 represents a targetable metabolic checkpoint of oncogenesis, which produces energy restriction effects via maintaining LONP1 K145 deacetylation and subsequent K63 ubiquitination.

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Deacetylation of Caveolin-1 by Sirt6 induces autophagy and retards high glucose-stimulated LDL transcytosis and atherosclerosis formation

Cited by 41 publications

References 51 publications

Polydatin Attenuates Cisplatin-Induced Acute Kidney Injury via SIRT6-Mediated Autophagy Activation

Polydatin Attenuates Cisplatin-Induced Acute Kidney Injury via SIRT6-Mediated Autophagy Activation

Integrated proteome and acetylome analyses unveil protein features of gestational diabetes mellitus and preeclampsia

Sirt3 restricts tumor initiation via promoting LONP1 deacetylation and K63 ubiquitination

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