Table 1.
The substrates and functions of SIRT6.
| SIRT6 function | Substrates | Molecular mechanism | Physiological functions | |
|---|---|---|---|---|
| Deacetylase | Histones | H3K9 | Inhibits NF-kB target gene expression | Prevents premature aging [160] |
| Inhibits 53BP1 binding to telomeres | Prevents telomere damage and delays VSMC senescence [78] | |||
| Facilitates loading of CHD4 onto DNA damage sites | Promotes chromatin relaxation and subsequent DNA repair [108] | |||
| Inhibits Nkx3.2 expression and thereby promotes GATA5 expression | Prevents hypertension and associated cardiorenal injury [66] | |||
| Inhibits HIF1α and associated glycolytic gene expression | Improves mitochondrial respiration and inhibits glycolysis against metabolic diseases [111] | |||
| Inhibits Notch1 and Notch4 expression | Protects podocytes from injury and attenuates proteinuria [245] | |||
| Inhibits expression of the proatherogenic gene TNFSF4 | Maintains endothelial function and protects against atherosclerosis [246] | |||
| Inhibits IGF signaling-related gene expression | Restricts the development of cardiac hypertrophy [68] | |||
| Inhibits c-Jun-dependent proinflammatory gene expression | Attenuates chronic liver inflammation and fibrosis [247] | |||
| Inhibits ERK1/2 expression | Attenuates cisplatin-induced kidney injury [248] | |||
| Facilitates binding of WRN with telomeres | Protects against telomere dysfunction and premature ageing disorders [249] | |||
| Inhibits NKG2D ligand expression in ECs | Stabilizes atherosclerotic plaques and restricts atherosclerosis [179] | |||
| Inhibits Txnip expression in β cells | Maintains pancreatic β-cell function and viability [124] | |||
| H3K56 | Inhibits β-catenin-dependent pro-fibrotic gene expression | Protects against kidney fibrosis following kidney ischemia-reperfusion injury [250] | ||
| Facilitates recruitment of the chromatin remodeler SNF2H to DSBs | Promotes DSB repair and genomic stability [236] | |||
| Facilitates recruitment of DNA repair proteins | Promotes the DDR process [106] | |||
| Inhibits catalase expression | Promotes neovascular injury by increasing ROS [72] | |||
| Promotes assembly of the Nrf2-RNAPII transcription complex at the HO-1 promoter, upregulating HO-1 expression | Facilitates ROS clearance to counteract oxidative stress injury [154] | |||
| H3K18 | Reduces levels of activated RNA Pol II and H3K36me3 | Protects against mitotic errors and cellular senescence [21] | ||
| Non- histones | SMAD2 (K54) | Reduces the transcriptional activity of SMAD2 | Protects against liver fibrosis [29] | |
| SMAD3 (K333/378) | Reduces the transcriptional activity of SMAD3 | Protects against liver fibrosis [30] | ||
| P53 (K381/382) | Inhibits P53 transcriptional activity | Ameliorates aging-associated phenotypes and attenuates cellular apoptosis [182, 224] | ||
| ERRγ (K195) | Promotes ERRγ degradation, thereby reducing Cyp7a1 expression | Attenuates cholestatic liver injury and fibrosis [251] | ||
| DDB2 (K35/77) | Promotes DDB2 ubiquitination and detachment from DNA lesions | Promotes the process of NER [102] | ||
| Mtf1 | Activates Mtf1 for the induction of Mt | Reduces oxidative stress and inflammation by inducing ROS [156] | ||
| SKP2 (K73/77) | Promotes SKP2 nuclear stability, thus increasing Suv39h1 ubiquitination and exclusion from chromatin, enabling H3K9me2 and H3S10p | Promotes expression of the NF-κB inhibitor IκBα to restrict the NF-κB pathway [162] | ||
| NAMPT (K53) | Promotes NAMPT enzymatic activity | Increases cellular NADPH levels to confer cell resistance to oxidative stress damage [27] | ||
| NPM1 | Inhibits NPM1 transcriptional activity and the expression of senescent genes | Inhibits cellular senescence [252] | ||
| PKM2 (K433) | Inhibits PKM2-induced STAT3 phosphorylation and activation | Suppresses macrophage polarization towards the proinflammatory M1 phenotype, inhibiting obesity-associated tissue inflammation and metabolic disorders [26, 144] | ||
| EZH2 | Promotes EZH2 DNA binding to promote FOXC1 expression | Ameliorates ischemic stroke-induced inflammation [214] | ||
| XBP1s (K257/297) | Promotes XBP1s degradation | Suppresses ER stress [28] | ||
| Caveolin-1 | Promotes autophagic degradation of Caveolin-1 | Ameliorates hyperglycemia-induced LDL transcytosis across ECs and atherosclerotic progression [171] | ||
| NFATc4 | Promotes NFATc4 nuclear export to inhibit BNP expression | Inhibits cardiac hypertrophy [189] | ||
| FoxO1 (K423) | Promotes FoxO1 nuclear export to increase expression of the glucose-sensing genes Pdx1 and Glut2 in pancreatic β-cells; inhibits PCK1 and G6PC expression in liver cells | Maintains the GSIS ability of β-cells and deceases gluconeogenesis to maintain glucose metabolic homeostasis [42, 120] | ||
| GCN5 (K549) | Promotes GCN5 activity to acetylate PGC-1α | Reduces hepatic gluconeogenesis [117] | ||
| Mono-ADP-ribosyltransferase | Non- histones | SIRT6 | May regulate Sirt6 enzymatic activity [31] | NR |
| KAP1 | Promotes SIRT6-KAP1-HP1α complex formation and heterochromatin packaging to decrease LINE1 expression | Inhibits genomic instability and senescence[33] | ||
| PARP1 (K521) | Activates PARP1 to recruit DNA repair factors | Promotes DNA damage repair [32] | ||
| KDM2A (R2020) | Promotes the displacement of KDM2A from chromatin | Promotes DNA damage repair, ensures replication fidelity [34] | ||
| BAF170 (K312) | Removes H3K27me3 and promotes chromatin accessibility to enhance HO-1 expression | Promotes the clearance of ROS to protect against cellular oxidative stress [35] | ||
| Long-chain fatty deacylase | Histones | H3 (K9/18/27/14/36/56/79) | May inhibit gene expression | NR |
| Non-histones | TNF-α (K19/20) | Promotes TNF-α secretion | Promotes inflammation [15] | |
| R-Ras2 (K192/194/196/197) | Suppresses R-Ras2 plasma membrane translocation and activation | Inhibits cell proliferation [38] | ||
| Non- catalytic activity | Non- histones | SIRT6-TIP60-GATA4 | Recruits TIP60 to acetylate GATA4 at K328/330; in turn, GATA4 inhibits the deacetylase activity of SIRT6 to promote TIP60-induced H3K9 acetylation, increasing expression of the anti-apoptotic gene Bcl-2 | Attenuates DOX-induced cardiomyocyte apoptosis [197] |
| SIRT6-Sp1-mTOR | Decreases Sp1 transcriptional activity to represses mTOR signaling gene expression | Regulates global cellular protein synthesis to combat cardiac hypertrophy [190] | ||
53BP1: p53-binding protein 1; VSMC: vascular smooth muscle cell; CHD4: chromodomain helicase DNA-binding protein 4; Nkx3.2: NK3 homeobox 2; GATA5: GATA-binding protein 5; TNFSF4: tumour necrosis factor superfamily member 4; IGF: insulin-like growth factor; ERK1/2: extracellular signal-regulated kinase 1/2; WRN: Werner syndrome helicase-nuclease; NKG2D: natural-killer group 2, number D; Txnip: thioredoxin-interacting protein; SNF2H: SWItch/sucrose nonfermentable catalytic subunit SNF2; DSBs: double-strand breaks; DDR: DNA damage response; Nrf2: nuclear factor erythroid-2 related factor 2; HO-1: haem oxygenase-1; SMAD2/3: nuclear translocation of mothers against decapentaplegic homologue 2/3; ERRγ: oestrogen-related receptor γ; Cyp7a1: cholesterol 7 α-hydroxylase; DDB2: DNA damage-binding protein 2; Mtf: metal transcription factor; Mt: metallothionein; SKP2: S phase kinase-associated protein 2; NPM1: nucleophosmin; Suv39h1:suppressor of variegation 3-9 homologue 1; PKM: M2 isoform of pyruvate kinase; STAT3: signal transducer and activator of transcription 3; FOXC1: Forkhead box C1; XBP1s: X-box-binding protein 1 spliced transcription factor; HMGB1: high mobility group box 1; NFATc4: nuclear factor of activated T cell 4; FoxO1: forkhead box protein O1; Pdx1: pancreatic duodenal homeobox 1; Glut2: glucose transporter 2; PCK1: phosphoenolpyruvate carboxykinase; G6PC; glucose-6-phosphatase; GSIS: glucose-stimulated insulin secretion; GCN5: general control nonrepressed protein 5; PGC-1α: peroxisome proliferator-activated receptor-γ coactivator 1-α; KAP1:KRAB-interacting protein 1; PARP1:poly ADP-ribose polymerase 1; LINE1: long interspersed nuclear element 1; KDM2A:lysine-specific demethylase 2; BAF170: BRG/BRM-associated factor (BAF) chromatin remodeler subunit; NRF2: nuclear factor erythroid 2-related factor 2; NR, not reported.