NOL3_RAT
ID NOL3_RAT Reviewed; 221 AA.
AC Q62881;
DT 02-MAY-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 118.
DE RecName: Full=Nucleolar protein 3;
DE AltName: Full=Apoptosis repressor with CARD;
GN Name=Nol3; Synonyms=Arc;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Sprague-Dawley; TISSUE=Brain, and Pheochromocytoma;
RX PubMed=8634331; DOI=10.1016/0167-4781(96)00036-x;
RA Geertman R., McMahon A., Sabban E.L.;
RT "Cloning and characterization of cDNAs for novel proteins with glutamic
RT acid-proline dipeptide tandem repeats.";
RL Biochim. Biophys. Acta 1306:147-152(1996).
RN [2]
RP FUNCTION, TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=10590251; DOI=10.1161/01.res.85.12.e70;
RA Ekhterae D., Lin Z., Lundberg M.S., Crow M.T., Brosius F.C. III, Nunez G.;
RT "ARC inhibits cytochrome c release from mitochondria and protects against
RT hypoxia-induced apoptosis in heart-derived H9c2 cells.";
RL Circ. Res. 85:E70-E77(1999).
RN [3]
RP INTERACTION WITH TFPT.
RX PubMed=10644725; DOI=10.1074/jbc.275.4.2647;
RA Irie Y., Yamagata K., Gan Y., Miyamoto K., Do E., Kuo C.H., Taira E.,
RA Miki N.;
RT "Molecular cloning and characterization of Amida, a novel protein which
RT interacts with a neuron-specific immediate early gene product arc, contains
RT novel nuclear localization signals, and causes cell death in cultured
RT cells.";
RL J. Biol. Chem. 275:2647-2653(2000).
RN [4]
RP IDENTIFICATION BY MASS SPECTROMETRY, PHOSPHORYLATION AT THR-149,
RP MUTAGENESIS OF THR-149, SUBCELLULAR LOCATION, AND FUNCTION.
RX PubMed=12191471; DOI=10.1016/s1097-2765(02)00600-7;
RA Li P.F., Li J., Mueller E.C., Otto A., Dietz R., von Harsdorf R.;
RT "Phosphorylation by protein kinase CK2: a signaling switch for the caspase-
RT inhibiting protein ARC.";
RL Mol. Cell 10:247-258(2002).
RN [5]
RP FUNCTION, INTERACTION WITH FADD; FAS; CASP8 AND BAX, MUTAGENESIS OF LEU-31
RP AND GLY-69, AND DOMAIN.
RX PubMed=15383280; DOI=10.1016/j.molcel.2004.08.020;
RA Nam Y.J., Mani K., Ashton A.W., Peng C.F., Krishnamurthy B., Hayakawa Y.,
RA Lee P., Korsmeyer S.J., Kitsis R.N.;
RT "Inhibition of both the extrinsic and intrinsic death pathways through
RT nonhomotypic death-fold interactions.";
RL Mol. Cell 15:901-912(2004).
RN [6]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH CASP2; BAX AND PPM1G, AND
RP MUTAGENESIS OF THR-149.
RX PubMed=16639714; DOI=10.1002/jcb.20946;
RA Zhang Y.Q., Herman B.;
RT "ARC protects rat cardiomyocytes against oxidative stress through
RT inhibition of caspase-2 mediated mitochondrial pathway.";
RL J. Cell. Biochem. 99:575-588(2006).
RN [7]
RP FUNCTION.
RX PubMed=17292893; DOI=10.1016/j.febslet.2007.01.050;
RA Hunter A.L., Zhang J., Chen S.C., Si X., Wong B., Ekhterae D., Luo H.,
RA Granville D.J.;
RT "Apoptosis repressor with caspase recruitment domain (ARC) inhibits
RT myogenic differentiation.";
RL FEBS Lett. 581:879-884(2007).
RN [8]
RP UBIQUITINATION.
RX PubMed=17142834; DOI=10.1074/jbc.m609046200;
RA Foo R.S., Chan L.K., Kitsis R.N., Bennett M.R.;
RT "Ubiquitination and degradation of the anti-apoptotic protein ARC by
RT MDM2.";
RL J. Biol. Chem. 282:5529-5535(2007).
RN [9]
RP DEPHOSPHORYLATION BY CALCINEURIN, PHOSPHORYLATION AT THR-149, AND
RP MUTAGENESIS OF THR-149.
RX PubMed=19001025; DOI=10.1161/circulationaha.107.750869;
RA Tan W.Q., Wang J.X., Lin Z.Q., Li Y.R., Lin Y., Li P.F.;
RT "Novel cardiac apoptotic pathway: the dephosphorylation of apoptosis
RT repressor with caspase recruitment domain by calcineurin.";
RL Circulation 118:2268-2276(2008).
RN [10]
RP INDUCTION, AND INTERACTION WITH BBC3 AND BAD.
RX PubMed=17998337; DOI=10.1128/mcb.00738-07;
RA Li Y.Z., Lu D.Y., Tan W.Q., Wang J.X., Li P.F.;
RT "p53 initiates apoptosis by transcriptionally targeting the antiapoptotic
RT protein ARC.";
RL Mol. Cell. Biol. 28:564-574(2008).
RN [11]
RP INDUCTION.
RX PubMed=22082675; DOI=10.1161/circulationaha.111.034512;
RA Zaiman A.L., Damico R., Thoms-Chesley A., Files D.C., Kesari P.,
RA Johnston L., Swaim M., Mozammel S., Myers A.C., Halushka M., El-Haddad H.,
RA Shimoda L.A., Peng C.F., Hassoun P.M., Champion H.C., Kitsis R.N.,
RA Crow M.T.;
RT "A critical role for the protein apoptosis repressor with caspase
RT recruitment domain in hypoxia-induced pulmonary hypertension.";
RL Circulation 124:2533-2542(2011).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-149, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
RN [13]
RP FUNCTION, INDUCTION, AND SUBCELLULAR LOCATION.
RX PubMed=23382383; DOI=10.1074/jbc.m112.442061;
RA Lu D., Liu J., Jiao J., Long B., Li Q., Tan W., Li P.;
RT "Transcription factor Foxo3a prevents apoptosis by regulating calcium
RT through the apoptosis repressor with caspase recruitment domain.";
RL J. Biol. Chem. 288:8491-8504(2013).
CC -!- FUNCTION: Apoptosis repressor that blocks multiple modes of cell death.
CC Inhibits extrinsic apoptotic pathways through two different ways.
CC Firstly by interacting with FAS and FADD upon FAS activation blocking
CC death-inducing signaling complex (DISC) assembly (PubMed:15383280).
CC Secondly by interacting with CASP8 in a mitochondria localization- and
CC phosphorylation-dependent manner, limiting the amount of soluble CASP8
CC available for DISC-mediated activation (PubMed:12191471). Inhibits
CC intrinsic apoptotic pathway in response to a wide range of stresses,
CC through its interaction with BAX resulting in BAX inactivation,
CC preventing mitochondrial dysfunction and release of pro-apoptotic
CC factors (PubMed:15383280). Inhibits calcium-mediated cell death by
CC functioning as a cytosolic calcium buffer, dissociating its interaction
CC with CASP8 and maintaining calcium homeostasis (PubMed:23382383).
CC Negatively regulates oxidative stress-induced apoptosis by
CC phosphorylation-dependent suppression of the mitochondria-mediated
CC intrinsic pathway, by blocking CASP2 activation and BAX translocation
CC (PubMed:16639714). Negatively regulates hypoxia-induced apoptosis in
CC part by inhibiting the release of cytochrome c from mitochondria in a
CC caspase-independent manner (PubMed:10590251). Also inhibits TNF-induced
CC necrosis by preventing TNF-signaling pathway through TNFRSF1A
CC interaction abrogating the recruitment of RIPK1 to complex I (By
CC similarity). Finally through its role as apoptosis repressor, promotes
CC vascular remodeling through inhibition of apoptosis and stimulation of
CC proliferation, in response to hypoxia (By similarity). Inhibits too
CC myoblast differentiation through caspase inhibition (PubMed:17292893).
CC {ECO:0000250|UniProtKB:O60936, ECO:0000250|UniProtKB:Q9D1X0,
CC ECO:0000269|PubMed:10590251, ECO:0000269|PubMed:12191471,
CC ECO:0000269|PubMed:15383280, ECO:0000269|PubMed:16639714,
CC ECO:0000269|PubMed:17292893, ECO:0000269|PubMed:23382383}.
CC -!- SUBUNIT: Oligomerizes (via CARD doamin) (By similarity). Interacts (via
CC CARD domain) with CASP2; inhibits CASP2 activity in a phosphorylation-
CC dependent manner. Interacts with CASP8; decreases CASP8 activity in a
CC mitochondria localization- and phosphorylation-dependent manner and
CC this interaction is dissociated by calcium. Interacts with TFPT;
CC translocates NOL3 into the nucleus and negatively regulated TFPT-
CC induced cell death. Interacts directly (via CARD domain) with FAS and
CC FADD (via DED domain); inhibits death-inducing signaling complex (DISC)
CC assembly by inhibiting the increase in FAS-FADD binding induced by FAS
CC activation. Interacts (via CARD domain) with BAX (via a C-terminal 33
CC residues); inhibits BAX activation and translocation and consequently
CC cytochrome c release from mitochondria. Interacts with PPM1G; may
CC dephosphorylate NOL3. Interacts (via CARD domain) with BBC3 (via BH3
CC domain); preventing the association of BBC3 with BCL2 and resulting in
CC activation of CASP8. Interacts (via CARD domain) with BAD(via BH3
CC domain); preventing the association of BAD with BCL2. Interacts
CC directly (via CARD domain) with TNFRSF1A; inhibits TNF-signaling
CC pathway (By similarity). {ECO:0000250|UniProtKB:O60936,
CC ECO:0000250|UniProtKB:Q9D1X0, ECO:0000269|PubMed:10644725,
CC ECO:0000269|PubMed:15383280, ECO:0000269|PubMed:16639714,
CC ECO:0000269|PubMed:17998337, ECO:0000305|PubMed:16639714}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:O60936,
CC ECO:0000269|PubMed:10590251, ECO:0000269|PubMed:12191471}.
CC Mitochondrion {ECO:0000269|PubMed:10590251,
CC ECO:0000269|PubMed:12191471, ECO:0000269|PubMed:16639714}. Sarcoplasmic
CC reticulum {ECO:0000269|PubMed:23382383}. Membrane
CC {ECO:0000250|UniProtKB:O60936}; Lipid-anchor
CC {ECO:0000250|UniProtKB:O60936}. Note=Phosphorylation at Thr-149 results
CC in translocation to mitochondria (PubMed:12191471). Colocalized with
CC mitochondria in response to oxidative stress (PubMed:16639714).
CC {ECO:0000269|PubMed:12191471, ECO:0000269|PubMed:16639714}.
CC -!- TISSUE SPECIFICITY: Highly expressed in skeletal muscle, heart and
CC medulla. {ECO:0000269|PubMed:10590251}.
CC -!- INDUCTION: Increased by chronic hypoxia (PubMed:22082675). Activated by
CC FOXO3 (PubMed:23382383). Negatively regulated by TP53
CC (PubMed:17998337). {ECO:0000269|PubMed:17998337,
CC ECO:0000269|PubMed:22082675, ECO:0000269|PubMed:23382383}.
CC -!- DOMAIN: CARD is critical for both extrinsic and intrinsic apoptotic
CC pathways (PubMed:15383280). CARD domain mediates a protective effect
CC against myocardial ischemia/reperfusion, oxidative stress and TNF-
CC induced necrosis (By similarity). The C-terminal domain (amino acids 99
CC to 221) is involved in calcium binding and plays a protective role in
CC calcium-mediated cell death (By similarity).
CC {ECO:0000250|UniProtKB:O60936, ECO:0000250|UniProtKB:Q9D1X0,
CC ECO:0000269|PubMed:15383280}.
CC -!- PTM: Phosphorylation at Thr-149 is required for its antiapoptotic
CC effect by blocking death-inducing signaling complex (DISC) activity
CC through the control of interaction with CASP8. Phosphorylation at Thr-
CC 149 results in translocation to mitochondria and this translocation
CC enables the binding to CASP8 (PubMed:12191471). Dephosphorylated at
CC Thr-149 by calcineurin; doesn't inhibit the association between FADD
CC and CASP8 and the consequent apoptosis (PubMed:19001025).
CC {ECO:0000269|PubMed:12191471, ECO:0000269|PubMed:19001025}.
CC -!- PTM: Polyubiquitinated by MDM2; promoting proteasomal-dependent
CC degradation in response to apoptotic stimuli.
CC {ECO:0000250|UniProtKB:O60936, ECO:0000269|PubMed:17142834}.
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DR EMBL; U40627; AAB05667.1; -; mRNA.
DR PIR; S70009; S70009.
DR RefSeq; NP_445968.2; NM_053516.2.
DR AlphaFoldDB; Q62881; -.
DR SMR; Q62881; -.
DR BioGRID; 250088; 2.
DR IntAct; Q62881; 1.
DR STRING; 10116.ENSRNOP00000020908; -.
DR iPTMnet; Q62881; -.
DR PhosphoSitePlus; Q62881; -.
DR SwissPalm; Q62881; -.
DR jPOST; Q62881; -.
DR PaxDb; Q62881; -.
DR PRIDE; Q62881; -.
DR GeneID; 85383; -.
DR KEGG; rno:85383; -.
DR UCSC; RGD:708558; rat.
DR CTD; 8996; -.
DR RGD; 708558; Nol3.
DR eggNOG; ENOG502SR4M; Eukaryota.
DR InParanoid; Q62881; -.
DR PhylomeDB; Q62881; -.
DR PRO; PR:Q62881; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0016020; C:membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0005730; C:nucleolus; ISS:UniProtKB.
DR GO; GO:0016528; C:sarcoplasm; ISO:RGD.
DR GO; GO:0016529; C:sarcoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0005509; F:calcium ion binding; ISO:RGD.
DR GO; GO:0089720; F:caspase binding; IPI:UniProtKB.
DR GO; GO:0043027; F:cysteine-type endopeptidase inhibitor activity involved in apoptotic process; ISO:RGD.
DR GO; GO:0035877; F:death effector domain binding; IPI:UniProtKB.
DR GO; GO:0005123; F:death receptor binding; ISO:RGD.
DR GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR GO; GO:0019900; F:kinase binding; IPI:UniProtKB.
DR GO; GO:0019902; F:phosphatase binding; IPI:UniProtKB.
DR GO; GO:0005102; F:signaling receptor binding; ISO:RGD.
DR GO; GO:0001974; P:blood vessel remodeling; ISO:RGD.
DR GO; GO:0010659; P:cardiac muscle cell apoptotic process; ISO:RGD.
DR GO; GO:0071456; P:cellular response to hypoxia; IDA:UniProtKB.
DR GO; GO:0097340; P:inhibition of cysteine-type endopeptidase activity; IDA:UniProtKB.
DR GO; GO:1990001; P:inhibition of cysteine-type endopeptidase activity involved in apoptotic process; ISO:RGD.
DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; ISO:RGD.
DR GO; GO:0006376; P:mRNA splice site selection; ISS:UniProtKB.
DR GO; GO:0045445; P:myoblast differentiation; IDA:UniProtKB.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:0010667; P:negative regulation of cardiac muscle cell apoptotic process; ISO:RGD.
DR GO; GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; IDA:UniProtKB.
DR GO; GO:0051481; P:negative regulation of cytosolic calcium ion concentration; IMP:UniProtKB.
DR GO; GO:1903073; P:negative regulation of death-inducing signaling complex assembly; IDA:UniProtKB.
DR GO; GO:2001237; P:negative regulation of extrinsic apoptotic signaling pathway; ISO:RGD.
DR GO; GO:1902042; P:negative regulation of extrinsic apoptotic signaling pathway via death domain receptors; IMP:UniProtKB.
DR GO; GO:1903206; P:negative regulation of hydrogen peroxide-induced cell death; IDA:UniProtKB.
DR GO; GO:1903298; P:negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway; IDA:UniProtKB.
DR GO; GO:2001243; P:negative regulation of intrinsic apoptotic signaling pathway; IMP:UniProtKB.
DR GO; GO:0051562; P:negative regulation of mitochondrial calcium ion concentration; IDA:UniProtKB.
DR GO; GO:1902109; P:negative regulation of mitochondrial membrane permeability involved in apoptotic process; ISO:RGD.
DR GO; GO:0014736; P:negative regulation of muscle atrophy; ISO:RGD.
DR GO; GO:0060547; P:negative regulation of necrotic cell death; ISO:RGD.
DR GO; GO:1902176; P:negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway; ISO:RGD.
DR GO; GO:1903215; P:negative regulation of protein targeting to mitochondrion; IDA:UniProtKB.
DR GO; GO:0090201; P:negative regulation of release of cytochrome c from mitochondria; IDA:UniProtKB.
DR GO; GO:0010664; P:negative regulation of striated muscle cell apoptotic process; ISO:RGD.
DR GO; GO:0010804; P:negative regulation of tumor necrosis factor-mediated signaling pathway; ISO:RGD.
DR GO; GO:0051259; P:protein complex oligomerization; ISS:UniProtKB.
DR GO; GO:0042981; P:regulation of apoptotic process; TAS:RGD.
DR GO; GO:0010468; P:regulation of gene expression; ISO:RGD.
DR GO; GO:1901222; P:regulation of NIK/NF-kappaB signaling; ISO:RGD.
DR GO; GO:0010880; P:regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum; IMP:UniProtKB.
DR GO; GO:0014808; P:release of sequestered calcium ion into cytosol by sarcoplasmic reticulum; ISO:RGD.
DR GO; GO:0001666; P:response to hypoxia; IEP:RGD.
DR GO; GO:0014876; P:response to injury involved in regulation of muscle adaptation; ISO:RGD.
DR GO; GO:0002931; P:response to ischemia; ISO:RGD.
DR GO; GO:0048659; P:smooth muscle cell proliferation; IMP:UniProtKB.
DR Gene3D; 1.10.533.10; -; 1.
DR InterPro; IPR001315; CARD.
DR InterPro; IPR011029; DEATH-like_dom_sf.
DR Pfam; PF00619; CARD; 1.
DR SMART; SM00114; CARD; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR PROSITE; PS50209; CARD; 1.
PE 1: Evidence at protein level;
KW Calcium; Cytoplasm; Lipoprotein; Membrane; Metal-binding; Mitochondrion;
KW mRNA processing; Myristate; Phosphoprotein; Reference proteome;
KW Sarcoplasmic reticulum; Ubl conjugation.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:O60936"
FT CHAIN 2..221
FT /note="Nucleolar protein 3"
FT /id="PRO_0000144101"
FT DOMAIN 4..95
FT /note="CARD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00046"
FT REGION 20..70
FT /note="Essential for interaction with BAX"
FT /evidence="ECO:0000269|PubMed:15383280"
FT REGION 107..221
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 145..166
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 167..221
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 149
FT /note="Phosphothreonine; by CK2"
FT /evidence="ECO:0000269|PubMed:12191471,
FT ECO:0007744|PubMed:22673903"
FT LIPID 2
FT /note="N-myristoyl glycine"
FT /evidence="ECO:0000250|UniProtKB:O60936"
FT MUTAGEN 31
FT /note="L->F: Failed to protect against extrinsic and
FT intrinsic apoptotic pathways; when associated with R-69.
FT Not interferes with death-inducing signaling complex (DISC)
FT assembly; when associated with R-69. Promotes BAX
FT activation; when associated with R-69."
FT /evidence="ECO:0000269|PubMed:15383280"
FT MUTAGEN 69
FT /note="G->R: Failed to protect against extrinsic and
FT intrinsic apoptotic pathways; when associated with F-31.
FT Not interferes with DISC assembly; when associated with F-
FT 31. Promotes BAX activation; when associated with F-31."
FT /evidence="ECO:0000269|PubMed:15383280"
FT MUTAGEN 149
FT /note="T->A: Not phosphorylated by CK2. Loses the ability
FT to block CASP8-, FAS-, or TNFRSF1A-induced apoptosis.
FT Prevents translocation to mitochondria. Significantly
FT decreases resistance to hydrogen peroxide-induced cell
FT death. Doesn't interact with PPM1G, BAX and CASP2. Doesn't
FT inhibit CASP2 and CASP3 activation. Doesn't was inhibit
FT CASP8-induced apoptosis."
FT /evidence="ECO:0000269|PubMed:12191471,
FT ECO:0000269|PubMed:16639714, ECO:0000269|PubMed:19001025"
FT MUTAGEN 149
FT /note="T->D: Significantly enhances resistance against
FT hydrogen peroxide- and induced by isoproterenol or
FT aldosterone-induced cell death."
FT /evidence="ECO:0000269|PubMed:16639714,
FT ECO:0000269|PubMed:19001025"
SQ SEQUENCE 221 AA; 24577 MW; A7661C9040B2CD4D CRC64;
MGNMQERPSE TIDRERKRLV ETLQADSGLL LDALVARGVL TGPEYEALDA LPDAERRVRR
LLLLVQSKGE AACQELLRCA QQTVSMPDPA WDWQHVGPGY RDRSYDPPCP GHWTPEAPSS
GTTCPGLPRA SEEEEIGGPE DSEAVQPRTP EEPELEAEAT KGDEPDLEQE MEPEPEPEVE
PEPEPEPEPE PEPEPEPEPE PEPEREPDFQ EGDESEGCEN T
