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FLASH GENE
Symbol SIRT4 contributors: mct - updated : 05-05-2020
HGNC name sirtuin (silent mating type information regulation 2 homolog) 4 (S. cerevisiae)
HGNC id 14932
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • a deacetylase sirtuin-type core domain
  • mono polymer complex
    HOMOLOGY
    interspecies homolog to yeast Sir2
    homolog to E.coli CobB
    ortholog to rattus Sirt4 predicted
    ortholog to murine Sirt4
    homolog to Drosophila sirt4
    Homologene
    FAMILY
  • sirtuin family
  • CATEGORY enzyme , regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria,inner
    intracellular,cytoplasm,organelle,mitochondria,matrix
    intracellular,cytoplasm,organelle,membrane
    text
  • matrix protein and becomes cleaved at amino acid 28 after import into mitochondria
  • mainly localized in the mitochondria
  • SIRT4 is localized to mitochondria within the brain
  • basic FUNCTION
  • by participating in the stress response to genomic insults, sirtuins are thought to protect against cancer, but they are also emerging as direct participants in the growth of some cancers
  • playing a role in the regulation of insulin secretion
  • lacks deacetylase activities but efficiently works as an ADP-ribosyltransferase
  • play a central role in epigenetic gene silencing, DNA repair and recombination, cell-cycle, microtubule organization, and in the regulation of aging
  • required to maintain cell survival after genotoxic stress in a NAD+-dependent manner
  • with SIRT3, modulate mitochondrial function in response to its [NADH]/[NAD+] ratio by regulating the activity of key metabolic enzymes
  • implicated in the regulation of insulin secretion by modulation of glutamate dehydrogenase
  • playing a role in regulating hepatic fat metabolism
  • is potentially a negative regulator of fat oxidation and overall mitochondrial oxidative metabolism
  • negative regulator of oxidative metabolism, which is in stark contrast to the functions of SIRT1 and SIRT3, which enhance the oxidative capacity of tissues
  • connected to keratinocyte differentiation, chronological aging, ultraviolet radiation (UVR) response, alopecia, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)
  • SIRT4 and GLUD1 overexpression play antagonistic roles in regulating gliogenesis
  • SIRT4 is an important regulator of lipid homeostasis
  • SIRT4 is a guardian of cellular metabolism
  • is a crucial regulator of the stress resistance of cancer cells
  • essential roles in stress resistance and may be an important therapeutic target for cancer treatment
  • SIRT4 is a crucial player maintaining insulin secretion and glucose homeostasis during aging
  • stress-responsive mitochondrial sirtuin SIRT4 controls cellular energy metabolism in a NAD+-dependent manner and is implicated in cellular senescence and aging
  • modulates energy homeostasis in multiple cell types and tissues
  • critical role for SIRT4 in the control of energy metabolism and meiotic apparatus during oocyte maturation and SIRT4 is an essential factor determining oocyte quality
  • in mitochondrial sirtuins, SIRT4 was the last of less well-understood mitochondrial sirtuins especially for its robust enzymatic activity
  • having robust deacylase activity in addition to the already accepted substrate-dependent lipoamidase and deacetylase properties
  • is proposed as either a mitochondrial tumor suppressor or a tumor-promoting protein in a context-dependent manner
  • CELLULAR PROCESS nucleotide, transcription, regulation
    protein, post translation
    PHYSIOLOGICAL PROCESS
    text chromatin silencing, protein ADP-ribosylation
    PATHWAY
    metabolism
    signaling
    a component
  • chromatin silencing complex
  • INTERACTION
    DNA binding
    RNA
    small molecule metal binding, cofactor,
  • Zn2+
  • NAD
  • protein
  • downregulating GLUD1
  • MLYCD is a SIRT4 target
  • SIRT4 regulates mitochondrial ATP homeostasis
  • ability of SIRT4 to regulate ATP levels via SLC25A5 and a feedback loop involving AMPK
  • is a cellular lipoamidase that regulates the pyruvate dehydrogenase complex (PDH)
  • CTBP1 have an essential role in promoting glutaminolysis by directly repressing the expression of SIRT4, a repressor of glutaminolysis by enzymatically modifying glutamate dehydrogenase in mitochondria, in cancer cells
  • SIRT4 interacts physically with OPA1, and SIRT4-OPA1 axis is causally linked to mitochondrial dysfunction and altered mitochondrial dynamics that translates into aging-associated decreased mitophagy based on an unbalanced mitochondrial fusion/fission cycle
  • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
             
    loss of SIRT4 in insulinoma cells activates GLUD1, thereby upregulating amino acid-stimulated insulin secretion
    tumoral     --low  
    in hepatocellular carcinoma tumour tissues, and the expression of SIRT4 in peritumour tissues was positively associated with survival in patients
    constitutional     --over  
    Protein levels of SIRT 4 were significantly higher in HUVECs from HELLP compared to control after 60 and 120 minutes of hypoxia
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    diabetetype 2 
    its inhibition increases fat oxidative capacity in liver and mitochondrial function in muscle, which might provide therapeutic benefits for diseases associated with ectopic lipid storage such as type 2 diabetes
    cancerdigestivecolon
    may serve as a novel therapeutic target in colorectal cancer
    ANIMAL & CELL MODELS
  • mouse oocytes overexpressing Sirt4 are unable to completely progress through meiosis, showing the inadequate mitochondrial redistribution, lowered ATP content, elevated reactive oxygen species (ROS) level, with the severely disrupted spindle/chromosome organization