InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: SIRT1

Summary

InnateDB Protein

IDBP-75849.7

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

SIRT1

Protein Name

sirtuin 1

Synonyms

SIR2L1;

Species

Homo sapiens

Ensembl Protein

ENSP00000212015

InnateDB Gene

IDBG-75847 (SIRT1)

Protein Structure

UniProt Annotation

Function

NAD-dependent protein deacetylase that links transcriptional regulation directly to intracellular energetics and participates in the coordination of several separated cellular functions such as cell cycle, response to DNA damage, metobolism, apoptosis and autophagy. Can modulate chromatin function through deacetylation of histones and can promote alterations in the methylation of histones and DNA, leading to transcriptional repression. Deacetylates a broad range of transcription factors and coregulators, thereby regulating target gene expression positively and negatively. Serves as a sensor of the cytosolic ratio of NAD(+)/NADH which is altered by glucose deprivation and metabolic changes associated with caloric restriction. Is essential in skeletal muscle cell differentiation and in response to low nutrients mediates the inhibitory effect on skeletal myoblast differentiation which also involves 5'-AMP-activated protein kinase (AMPK) and nicotinamide phosphoribosyltransferase (NAMPT). Component of the eNoSC (energy-dependent nucleolar silencing) complex, a complex that mediates silencing of rDNA in response to intracellular energy status and acts by recruiting histone-modifying enzymes. The eNoSC complex is able to sense the energy status of cell: upon glucose starvation, elevation of NAD(+)/NADP(+) ratio activates SIRT1, leading to histone H3 deacetylation followed by dimethylation of H3 at 'Lys-9' (H3K9me2) by SUV39H1 and the formation of silent chromatin in the rDNA locus. Deacetylates 'Lys-266' of SUV39H1, leading to its activation. Inhibits skeletal muscle differentiation by deacetylating PCAF and MYOD1. Deacetylates H2A and 'Lys-26' of HIST1H1E. Deacetylates 'Lys-16' of histone H4 (in vitro). Involved in NR0B2/SHP corepression function through chromatin remodeling: Recruited to LRH1 target gene promoters by NR0B2/SHP thereby stimulating histone H3 and H4 deacetylation leading to transcriptional repression. Proposed to contribute to genomic integrity via positive regulation of telomere length; however, reports on localization to pericentromeric heterochromatin are conflicting. Proposed to play a role in constitutive heterochromatin (CH) formation and/or maintenance through regulation of the available pool of nuclear SUV39H1. Upon oxidative/metabolic stress decreases SUV39H1 degradation by inhibiting SUV39H1 polyubiquitination by MDM2. This increase in SUV39H1 levels enhances SUV39H1 turnover in CH, which in turn seems to accelerate renewal of the heterochromatin which correlates with greater genomic integrity during stress response. Deacetylates 'Lys-382' of p53/TP53 and impairs its ability to induce transcription-dependent proapoptotic program and modulate cell senescence. Deacetylates TAF1B and thereby represses rDNA transcription by the RNA polymerase I. Deacetylates MYC, promotes the association of MYC with MAX and decreases MYC stability leading to compromised transformational capability. Deacetylates FOXO3 in response to oxidative stress thereby increasing its ability to induce cell cycle arrest and resistance to oxidative stress but inhibiting FOXO3-mediated induction of apoptosis transcriptional activity; also leading to FOXO3 ubiquitination and protesomal degradation. Appears to have a similar effect on MLLT7/FOXO4 in regulation of transcriptional activity and apoptosis. Deacetylates DNMT1; thereby impairs DNMT1 methyltransferase-independent transcription repressor activity, modulates DNMT1 cell cycle regulatory function and DNMT1-mediated gene silencing. Deacetylates RELA/NF-kappa-B p65 thereby inhibiting its transactivating potential and augments apoptosis in response to TNF-alpha. Deacetylates HIF1A, KAT5/TIP60, RB1 and HIC1. Deacetylates FOXO1 resulting in its nuclear retention and enhancement of its transcriptional activity leading to increased gluconeogenesis in liver. Inhibits E2F1 transcriptional activity and apoptotic function, possibly by deacetylation. Involved in HES1- and HEY2-mediated transcriptional repression. In cooperation with MYCN seems to be involved in transcriptional repression of DUSP6/MAPK3 leading to MYCN stabilization by phosphorylation at 'Ser-62'. Deacetylates MEF2D. Required for antagonist-mediated transcription suppression of AR-dependent genes which may be linked to local deacetylation of histone H3. Represses HNF1A- mediated transcription. Required for the repression of ESRRG by CREBZF. Modulates AP-1 transcription factor activity. Deacetylates NR1H3 AND NR1H2 and deacetylation of NR1H3 at 'Lys-434' positively regulates transcription of NR1H3:RXR target genes, promotes NR1H3 proteosomal degradation and results in cholesterol efflux; a promoter clearing mechanism after reach round of transcription is proposed. Involved in lipid metabolism. Implicated in regulation of adipogenesis and fat mobilization in white adipocytes by repression of PPARG which probably involves association with NCOR1 and SMRT/NCOR2. Deacetylates ACSS2 leading to its activation, and HMGCS1. Involved in liver and muscle metabolism. Through deacteylation and activation of PPARGC1A is required to activate fatty acid oxidation in skeletel muscle under low-glucose conditions and is involved in glucose homeostasis. Involved in regulation of PPARA and fatty acid beta-oxidation in liver. Involved in positive regulation of insulin secretion in pancreatic beta cells in response to glucose; the function seems to imply transcriptional repression of UCP2. Proposed to deacetylate IRS2 thereby facilitating its insulin-induced tyrosine phosphorylation. Deacetylates SREBF1 isoform SREBP-1C thereby decreasing its stability and transactivation in lipogenic gene expression. Involved in DNA damage response by repressing genes which are involved in DNA repair, such as XPC and TP73, deacetylating XRCC6/Ku70, and faciliting recruitment of additional factors to sites of damaged DNA, such as SIRT1-deacetylated NBN can recruit ATM to initiate DNA repair and SIRT1-deacetylated XPA interacts with RPA2. Also involved in DNA repair of DNA double-strand breaks by homologous recombination and specifically single-strand annealing independently of XRCC6/Ku70 and NBN. Transcriptional suppression of XPC probably involves an E2F4:RBL2 suppressor complex and protein kinase B (AKT) signaling. Transcriptional suppression of TP73 probably involves E2F4 and PCAF. Deacetylates WRN thereby regulating its helicase and exonuclease activities and regulates WRN nuclear translocation in response to DNA damage. Deacetylates APEX1 at 'Lys-6' and 'Lys-7' and stimulates cellular AP endonuclease activity by promoting the association of APEX1 to XRCC1. Increases p53/TP53-mediated transcription-independent apoptosis by blocking nuclear translocation of cytoplasmic p53/TP53 and probably redirecting it to mitochondria. Deacetylates XRCC6/Ku70 at 'Lys-539' and 'Lys-542' causing it to sequester BAX away from mitochondria thereby inhibiting stress-induced apoptosis. Is involved in autophagy, presumably by deacetylating ATG5, ATG7 and MAP1LC3B/ATG8. Deacetylates AKT1 which leads to enhanced binding of AKT1 and PDK1 to PIP3 and promotes their activation. Proposed to play role in regulation of STK11/LBK1- dependent AMPK signaling pathways implicated in cellular senescence which seems to involve the regulation of the acetylation status of STK11/LBK1. Can deacetylate STK11/LBK1 and thereby increase its activity, cytoplasmic localization and association with STRAD; however, the relevance of such activity in normal cells is unclear. In endothelial cells is shown to inhibit STK11/LBK1 activity and to promote its degradation. Deacetylates SMAD7 at 'Lys-64' and 'Lys-70' thereby promoting its degradation. Deacetylates CIITA and augments its MHC class II transactivation and contributes to its stability. Deacteylates MECOM/EVI1. Isoform 2 is shown to deacetylate 'Lys-382' of p53/TP53, however with lower activity than isoform 1. In combination, the two isoforms exert an additive effect. Isoform 2 regulates p53/TP53 expression and cellular stress response and is in turn repressed by p53/TP53 presenting a SIRT1 isoform-dependent auto-regulatory loop. In case of HIV-1 infection, interacts with and deacetylates the viral Tat protein. The viral Tat protein inhibits SIRT1 deacetylation activity toward RELA/NF-kappa-B p65, thereby potentiates its transcriptional activity and SIRT1 is proposed to contribute to T- cell hyperactivation during infection. Deacetylates PML at 'Lys- 487' and this deacetylation promotes PML control of PER2 nuclear localization. During the neurogenic transition, repress selective NOTCH1-target genes through histone deacetylation in a BCL6- dependent manner and leading to neuronal differentiation.SirtT1 75 kDa fragment: catalytically inactive 75SirT1 may be involved in regulation of apoptosis. May be involved in protecting chondrocytes from apoptotic death by associating with cytochrome C and interfering with apoptosome assembly.

Subcellular Localization

Nucleus, PML body. Cytoplasm. Note=Recruited to the nuclear bodies via its interaction with PML. Colocalized with APEX1 in the nucleus. May be found in nucleolus, nuclear euchromatin, heterochromatin and inner membrane. Shuttles between nucleus and cytoplasm.SirtT1 75 kDa fragment: Cytoplasm. Mitochondrion.

Disease Associations

Tissue Specificity

Widely expressed. {ECO:0000269PubMed:10381378}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 383 experimentally validated interaction(s) in this database.
They are also associated with 47 interaction(s) predicted by orthology.

Experimentally validated
Total	383 [view]
Protein-Protein	268 [view]
Protein-DNA	6 [view]
Protein-RNA	1 [view]
DNA-DNA	108 [view]
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	47 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0002039	p53 binding
GO:0003714	transcription corepressor activity
GO:0004407	histone deacetylase activity
GO:0005515	protein binding
GO:0008022	protein C-terminus binding
GO:0008134	transcription factor binding
GO:0017136	NAD-dependent histone deacetylase activity
GO:0019213	deacetylase activity
GO:0019899	enzyme binding
GO:0033558	protein deacetylase activity
GO:0034979	NAD-dependent protein deacetylase activity
GO:0042393	histone binding
GO:0042802	identical protein binding
GO:0043398	HLH domain binding
GO:0043425	bHLH transcription factor binding
GO:0046872	metal ion binding
GO:0046969	NAD-dependent histone deacetylase activity (H3-K9 specific)
GO:0051019	mitogen-activated protein kinase binding
GO:0070403	NAD+ binding
GO:1990254	keratin filament binding

Biological Process

GO:0000012	single strand break repair
GO:0000122	negative regulation of transcription from RNA polymerase II promoter
GO:0000183	chromatin silencing at rDNA
GO:0000720	pyrimidine dimer repair by nucleotide-excision repair
GO:0000731	DNA synthesis involved in DNA repair
GO:0001525	angiogenesis
GO:0001542	ovulation from ovarian follicle
GO:0001678	cellular glucose homeostasis
GO:0001934	positive regulation of protein phosphorylation
GO:0002821	positive regulation of adaptive immune response
GO:0006260	DNA replication
GO:0006281	DNA repair
GO:0006325	chromatin organization
GO:0006342	chromatin silencing
GO:0006343	establishment of chromatin silencing
GO:0006344	maintenance of chromatin silencing
GO:0006346	methylation-dependent chromatin silencing
GO:0006351	transcription, DNA-templated
GO:0006364	rRNA processing
GO:0006476	protein deacetylation
GO:0006642	triglyceride mobilization
GO:0006974	cellular response to DNA damage stimulus
GO:0006979	response to oxidative stress
GO:0007283	spermatogenesis
GO:0007346	regulation of mitotic cell cycle
GO:0007517	muscle organ development
GO:0007569	cell aging
GO:0008284	positive regulation of cell proliferation
GO:0009267	cellular response to starvation
GO:0010875	positive regulation of cholesterol efflux
GO:0010906	regulation of glucose metabolic process
GO:0016032	viral process
GO:0016239	positive regulation of macroautophagy
GO:0016567	protein ubiquitination
GO:0016575	histone deacetylation
GO:0018394	peptidyl-lysine acetylation
GO:0030308	negative regulation of cell growth
GO:0030512	negative regulation of transforming growth factor beta receptor signaling pathway
GO:0031393	negative regulation of prostaglandin biosynthetic process
GO:0031648	protein destabilization
GO:0031667	response to nutrient levels
GO:0031937	positive regulation of chromatin silencing
GO:0032007	negative regulation of TOR signaling
GO:0032071	regulation of endodeoxyribonuclease activity
GO:0032088	negative regulation of NF-kappaB transcription factor activity
GO:0032868	response to insulin
GO:0033158	regulation of protein import into nucleus, translocation
GO:0034391	regulation of smooth muscle cell apoptotic process
GO:0034983	peptidyl-lysine deacetylation
GO:0035356	cellular triglyceride homeostasis
GO:0035358	regulation of peroxisome proliferator activated receptor signaling pathway
GO:0042127	regulation of cell proliferation
GO:0042326	negative regulation of phosphorylation
GO:0042542	response to hydrogen peroxide
GO:0042632	cholesterol homeostasis
GO:0042771	intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator
GO:0043065	positive regulation of apoptotic process
GO:0043066	negative regulation of apoptotic process
GO:0043124	negative regulation of I-kappaB kinase/NF-kappaB signaling
GO:0043161	proteasome-mediated ubiquitin-dependent protein catabolic process
GO:0043280	positive regulation of cysteine-type endopeptidase activity involved in apoptotic process
GO:0043433	negative regulation of sequence-specific DNA binding transcription factor activity
GO:0043518	negative regulation of DNA damage response, signal transduction by p53 class mediator
GO:0045087	innate immune response (InnateDB)
GO:0045348	positive regulation of MHC class II biosynthetic process
GO:0045599	negative regulation of fat cell differentiation
GO:0045739	positive regulation of DNA repair
GO:0045892	negative regulation of transcription, DNA-templated
GO:0045944	positive regulation of transcription from RNA polymerase II promoter
GO:0046628	positive regulation of insulin receptor signaling pathway
GO:0050872	white fat cell differentiation
GO:0051097	negative regulation of helicase activity
GO:0051574	positive regulation of histone H3-K9 methylation
GO:0051898	negative regulation of protein kinase B signaling
GO:0055089	fatty acid homeostasis
GO:0060766	negative regulation of androgen receptor signaling pathway
GO:0070301	cellular response to hydrogen peroxide
GO:0070857	regulation of bile acid biosynthetic process
GO:0070932	histone H3 deacetylation
GO:0071356	cellular response to tumor necrosis factor
GO:0071456	cellular response to hypoxia
GO:0071479	cellular response to ionizing radiation
GO:1901215	negative regulation of neuron death
GO:1902166	negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator
GO:1902176	negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway
GO:2000111	positive regulation of macrophage apoptotic process
GO:2000480	negative regulation of cAMP-dependent protein kinase activity
GO:2000481	positive regulation of cAMP-dependent protein kinase activity
GO:2000655	negative regulation of cellular response to testosterone stimulus
GO:2000757	negative regulation of peptidyl-lysine acetylation
GO:2000773	negative regulation of cellular senescence
GO:2000774	positive regulation of cellular senescence

Cellular Component

GO:0000790	nuclear chromatin
GO:0005634	nucleus
GO:0005635	nuclear envelope
GO:0005637	nuclear inner membrane
GO:0005654	nucleoplasm
GO:0005677	chromatin silencing complex
GO:0005719	nuclear euchromatin
GO:0005720	nuclear heterochromatin
GO:0005730	nucleolus
GO:0005737	cytoplasm
GO:0005739	mitochondrion
GO:0016605	PML body
GO:0033553	rDNA heterochromatin
GO:0035098	ESC/E(Z) complex