Protein: Forkhead box protein O (FOXO) (Abnormal dauer formation protein 16) (O16850)
Organism: Caenorhabditis elegans
Function: Forkhead-type transcription factor. Binds to the promoters of genes that contain the daf-16/FOXO binding element (DBE), TTGTTTAC, in their regulatory region. Functions in the Insulin/IGF-1-like signaling (IIS) mediated pathway which affects lipogenesis, lifespan, starvation survival, heat shock and oxidative stress responses, sleep, associative memory, and dauer formation. Longevity signaling predominantly arises from expression in the intestine. Transcriptional activity of daf-16/FOXO is negatively regulated by interaction with host cell factor homolog hcf-1; and by cytoplasmic sequestration by association with ftt-2. Inhibition is required for the carbon dioxide (CO2) avoidance response. Upon loss of inhibition, daf-16 translocates to the nucleus to regulate genes that result in delayed reproduction and growth while increasing stress resistance starvation tolerance and longevity. Association with arginine methyltransferase prmt-1 prevents phosphorylation and allows for translocation to the nucleus and the subsequent transcription of longevity-related genes. Modulation of its activity by cGMP levels in sensory neurons regulates lifespan. Has a protective role against muscle dystrophy. Involved in mediating protection against aberrant protein aggregation proteotoxicity. Influences transcription of genes that code for proteins involved in immunity as part of a general stress response. Targets genes that inhibit and stimulate tumor growth. Targets kinases, phosphatases and transcription factors that are primarily involved in signaling and gene regulation. Thought to regulate ins-7 in FOXO-to-FOXO signaling, which coordinates daf-16 expression. Activity is positively regulated by shc-1-mediated inhibition of daf-2 and activation of JNK pathway. Through the regulation of its activity by shc-1-mediated inhibition of daf-2 and activation of JNK pathway, plays a role in maintaining the integrity of the gonad. Functions by indirect interaction with jnk-1 of the mitogen-activated protein kinase (MAPK) pathway. Involved in increased proteasome activity by activating expression of rpn-6.1 in response to proteotoxic stress, leading to enhanced assembly of the 26S proteasome, followed by higher proteasome activity. Also regulates proteasome activity in the intestine by preventing expression of deubiquitinase ubh-4. Represses transcription of natc-1. Involved in regulation of srh-234 expression. Binds to the promoter of the AMPK-gamma regulatory subunit, aakg-4, and activates its transcription. Also activates transcription of AMPK-gamma regulatory subunit, aakg-1. Maintains endoplasmic reticulum (ER) function by inducing protein degradation and elimination to remove misfolded secretory proteins from the ER independently of the ire-1/xbp-1 unfolded protein response pathway. Regulates epidermal innate immunity to nematophagous fungal infection and physical wounding which trigger bli-3 induced ROS release, leading to daf-16 activation independently of daf-2 signaling. May negatively regulate resistance to stress caused by oxidized cholesterol adducts by preventing the activation of daf-9 and nuclear hormone receptor daf-12, two members of the steroid signaling pathway. Promotes apoptosis during embryonic development. Probably through the regulation of the autophagy genes atg-18 and atg-16.2, plays a role in regulating stem cell number in the germline during larval development. Plays a role in learning and memory; including associative memory, and aversive gustatory associated learning known as salt avoidance learning. Plays a role in regulating gene transcription in response to white light exposure. Binds to the promoter of dex-1 to positively regulate its expression in seam cells during the dauer phase. Plays a role in transgenerational lipid accumulation in response to a high-fat diet.
Subcellular location: Nucleus {ECO:0000269|PubMed:11381260, ECO:0000269|PubMed:11747825, ECO:0000269|PubMed:15767565, ECO:0000269|PubMed:15888317, ECO:0000269|PubMed:17551714, ECO:0000269|PubMed:17894411, ECO:0000269|PubMed:18832074, ECO:0000269|PubMed:19252938, ECO:0000269|PubMed:21531333, ECO:0000269|PubMed:22916022, ECO:0000269|PubMed:23805378, ECO:0000269|PubMed:24146615}. Cytoplasm {ECO:0000269|PubMed:11381260, ECO:0000269|PubMed:11747825, ECO:0000269|PubMed:15767565, ECO:0000269|PubMed:15888317, ECO:0000269|PubMed:17551714, ECO:0000269|PubMed:17894411, ECO:0000269|PubMed:18832074, ECO:0000269|PubMed:19252938, ECO:0000269|PubMed:21531333, ECO:0000269|PubMed:22916022, ECO:0000269|PubMed:23805378, ECO:0000269|PubMed:24146615}. Note=Shuttles between cytoplasm and nucleus (PubMed:11381260, PubMed:17894411). Nuclear translocation is inhibited by phosphorylation by AKT proteins (PubMed:11381260, PubMed:11747825, PubMed:21531333). Association with ftt-2 sequesters daf-16 in the cytoplasm (PubMed:21531333). Association with prmt-1 allows for translocation to the nucleus (PubMed:21531333). Nuclear translocation is promoted by phosphorylation by unc-43 and inhibited by dephosphorylation by tax-6 (PubMed:23805378). Nuclear translocation is promoted by jnk-1 upon heat stress and by sek-1 upon oxidative stress (PubMed:15767565, PubMed:15888317). Nucleocytoplasmic shuttling is induced by starvation, heat treatment, hypergravity, reactive oxygen species (generated by juglone), exposure to tributyltin or 4-hydroxy-E-globularinin (4-HEG) and the flavonoids kaempferol and fisetin (PubMed:11381260, PubMed:17551714, PubMed:18832074, PubMed:19252938, PubMed:21531333, PubMed:23805378). Nuclear localization induced by nematophagous fungal infection (PubMed:24146615). {ECO:0000269|PubMed:11381260, ECO:0000269|PubMed:11747825, ECO:0000269|PubMed:15767565, ECO:0000269|PubMed:15888317, ECO:0000269|PubMed:17551714, ECO:0000269|PubMed:17894411, ECO:0000269|PubMed:18832074, ECO:0000269|PubMed:19252938, ECO:0000269|PubMed:21531333, ECO:0000269|PubMed:24146615}.; SUBCELLULAR LOCATION: [Isoform a]: Nucleus {ECO:0000269|PubMed:24834345}. Cytoplasm {ECO:0000269|PubMed:24834345}. Note=Ratio of nuclear to cytoplasmic localization is daf-2-dependent. {ECO:0000269|PubMed:24834345}.; SUBCELLULAR LOCATION: [Isoform d]: Nucleus {ECO:0000269|PubMed:24834345}. Cytoplasm {ECO:0000269|PubMed:24834345}. Note=Ratio of nuclear to cytoplasmic localization is daf-2-dependent. {ECO:0000269|PubMed:24834345}.; SUBCELLULAR LOCATION: [Isoform f]: Nucleus {ECO:0000269|PubMed:24834345}. Cytoplasm {ECO:0000269|PubMed:24834345}. Note=Ratio of nuclear to cytoplasmic localization is daf-2-dependent. {ECO:0000269|PubMed:24834345}.
Interaction partners:
- Serine/threonine-protein kinase akt-1
- NAD-dependent protein deacetylase sir-2.1
- Serine/threonine-protein kinase akt-2
- Insulin-like receptor
- Serine/threonine-protein kinase sgk-1
- Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase daf-18
- 5'-AMP-activated protein kinase catalytic subunit alpha-2
- Phosphatidylinositol 3-kinase age-1
- Mitogen-activated protein kinase pmk-1
- 14-3-3-like protein 2
Sequence:
MQLEQKSSLHCSKCRNFLQKFSQDMQAWNCRELDSPLPSDITLHNLEPARPDSGMSFSTDFDDDFFNLDLHQQERSASFGGVTQYSQQFLREKCSFSPYFHTSLETVDSGRTSLYGSNEQCGQLGGASSNGSTAMLHTPDGSNSHQTSFPSDFRMSESPDDTVSGKKTTTRRNAWGNMSYAELITTAIMASPEKRLTLAQVYEWMVQNVPYFRDKGDSNSSAGWKNSIRHNLSLHSRFMRIQNEGAGKSSWWVINPDAKPGRNPRRTRERSNTIETTTKAQLEKSRRGAKKRIKERALMGSLHSTLNGNSIAGSIQTISHDLYDDDSMQGAFDNVPSSFRPRTQSNLSIPGSSSRVSPAIGSDIYDDLEFPSWVGESVPAIPSDIVDRTDQMRIDATTHIGGVQIKQESKPIKTEPIAPPPSYHELNSVRGSCAQNPLLRNPIVPSTNFKPMPLPGAYGNYQNGGITPINWLSTSNSSPLPGIQSCGIVAAQHTVASSSALPIDLENLTLPDQPLMDTMDVDALIRHELSQAGGQHIHFDL