NOL3_MOUSE
ID NOL3_MOUSE Reviewed; 220 AA.
AC Q9D1X0;
DT 02-MAY-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2001, sequence version 1.
DT 03-AUG-2022, entry version 136.
DE RecName: Full=Nucleolar protein 3 {ECO:0000312|MGI:MGI:1925938};
DE AltName: Full=Apoptosis repressor with CARD {ECO:0000305|PubMed:16505176};
GN Name=Nol3; Synonyms=Arc;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Adipose tissue;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [2]
RP INTERACTION WITH FADD; FAS; CASP8 AND BAX.
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 [3]
RP DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=16505176; DOI=10.1161/circulationaha.105.576785;
RA Donath S., Li P., Willenbockel C., Al-Saadi N., Gross V., Willnow T.,
RA Bader M., Martin U., Bauersachs J., Wollert K.C., Dietz R.,
RA von Harsdorf R.;
RT "Apoptosis repressor with caspase recruitment domain is required for
RT cardioprotection in response to biomechanical and ischemic stress.";
RL Circulation 113:1203-1212(2006).
RN [4]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Lung, Pancreas, and
RC Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [5]
RP FUNCTION.
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 [6]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=24312627; DOI=10.1371/journal.pone.0082053;
RA Davis J., Kwong J.Q., Kitsis R.N., Molkentin J.D.;
RT "Apoptosis repressor with a CARD domain (ARC) restrains Bax-mediated
RT pathogenesis in dystrophic skeletal muscle.";
RL PLoS ONE 8:E82053-E82053(2013).
RN [7]
RP FUNCTION, INTERACTION WITH TNFRSF1A, AND MUTAGENESIS OF LEU-31 AND GLY-69.
RX PubMed=24440909; DOI=10.1038/cdd.2013.195;
RA Kung G., Dai P., Deng L., Kitsis R.N.;
RT "A novel role for the apoptosis inhibitor ARC in suppressing TNFalpha-
RT induced regulated necrosis.";
RL Cell Death Differ. 21:634-644(2014).
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 (By similarity).
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 (By similarity). 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:16505176) (PubMed:24312627). Inhibits calcium-mediated
CC cell death by functioning as a cytosolic calcium buffer, dissociating
CC its interaction with CASP8 and maintaining calcium homeostasis (By
CC similarity). 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 (By similarity). Negatively regulates hypoxia-induced apoptosis in part
CC by inhibiting the release of cytochrome c from mitochondria in a
CC caspase-independent manner (By similarity). Also inhibits TNF-induced
CC necrosis by preventing TNF-signaling pathway through TNFRSF1A
CC interaction abrogating the recruitment of RIPK1 to complex I
CC (PubMed:24440909). Finally through its role as apoptosis repressor,
CC promotes vascular remodeling through inhibition of apoptosis and
CC stimulation of proliferation, in response to hypoxia (PubMed:22082675).
CC Inhibits too myoblast differentiation through caspase inhibition (By
CC similarity). {ECO:0000250, ECO:0000250|UniProtKB:O60936,
CC ECO:0000250|UniProtKB:Q62881, ECO:0000269|PubMed:16505176,
CC ECO:0000269|PubMed:22082675, ECO:0000269|PubMed:24312627,
CC ECO:0000269|PubMed:24440909}.
CC -!- SUBUNIT: Oligomerizes (via CARD doamin) (By similarity). Interacts (via
CC CARD domain) with CASP2; inhibits CASP2 activity in a phosphorylation-
CC dependent manner (By similarity). Interacts with CASP8; decreases CASP8
CC activity in a mitochondria localization- and phosphorylation-dependent
CC manner and this interaction is dissociated by calcium. Interacts with
CC TFPT; translocates NOL3 into the nucleus and negatively regulated TFPT-
CC induced cell death (By similarity). Interacts directly (via CARD
CC domain) with FAS and FADD (via DED domain); inhibits death-inducing
CC signaling complex (DISC) assembly by inhibiting the increase in FAS-
CC FADD binding induced by FAS activation. Interacts (via CARD domain)
CC with BAX (via a C-terminal 33 residues); inhibits BAX activation and
CC translocation and consequently cytochrome c release from mitochondria.
CC Interacts with PPM1G; may dephosphorylate NOL3 (By similarity).
CC Interacts (via CARD domain) with BBC3 (via BH3 domain); preventing the
CC association of BBC3 with BCL2 and resulting in activation of CASP8 (By
CC similarity). Interacts (via CARD domain) with BAD(via BH3 domain);
CC preventing the association of BAD with BCL2 (By similarity). Interacts
CC directly (via CARD domain) with TNFRSF1A; inhibits TNF-signaling
CC pathway. {ECO:0000250|UniProtKB:O60936, ECO:0000250|UniProtKB:Q62881,
CC ECO:0000269|PubMed:15383280, ECO:0000269|PubMed:24440909}.
CC -!- INTERACTION:
CC Q9D1X0; Q6PFR5: Tra2a; NbExp=4; IntAct=EBI-913097, EBI-913075;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:O60936,
CC ECO:0000250|UniProtKB:Q62881}. Mitochondrion
CC {ECO:0000250|UniProtKB:Q62881}. Sarcoplasmic reticulum
CC {ECO:0000250|UniProtKB:Q62881}. Membrane
CC {ECO:0000250|UniProtKB:O60936}; Lipid-anchor
CC {ECO:0000250|UniProtKB:O60936}. Note=Phosphorylation at Thr-149 results
CC in translocation to mitochondria. Colocalized with mitochondria in
CC response to oxidative stress. {ECO:0000250|UniProtKB:Q62881}.
CC -!- DOMAIN: CARD is critical for both extrinsic and intrinsic apoptotic
CC pathways (By similarity). CARD domain mediates a protective effect
CC against myocardial ischemia/reperfusion, oxidative stress and TNF-
CC induced necrosis (PubMed:24440909). The C-terminal domain (amino acids
CC 99 to 220) is involved in calcium binding and plays a protective role
CC in calcium-mediated cell death (By similarity).
CC {ECO:0000250|UniProtKB:O60936, ECO:0000250|UniProtKB:Q62881,
CC ECO:0000269|PubMed:24440909}.
CC -!- PTM: Phosphorylation at Thr-149 is required for its antiapoptotic
CC effect by blocking death-inducing signaling complex death-inducing
CC signaling complex (DISC) activity through the control of interaction
CC with CASP8. Phosphorylation at Thr-149 results in translocation to
CC mitochondria and this translocation enables the binding to CASP8.
CC Dephosphorylated at Thr-149 by calcineurin; doesn't inhibit the
CC association between FADD and CASP8 and the consequent apoptosis.
CC {ECO:0000250|UniProtKB:Q62881}.
CC -!- PTM: Polyubiquitinated by MDM2; promoting proteasomal-dependent
CC degradation in response to apoptotic stimuli.
CC {ECO:0000250|UniProtKB:O60936, ECO:0000250|UniProtKB:Q62881}.
CC -!- DISRUPTION PHENOTYPE: Mice homozygous for the NOL3-null allele are born
CC normally and externally indistinguishable from littermates of other
CC genotypes. NOL3-null mice grew to adulthood without any abnormalities
CC in their general health and appearance under resting conditions. Under
CC biomechanical stress, NOL3-deficient mice develop accelerated
CC cardiomyopathy which is characterized by reduced contractile function,
CC cardiac enlargement, and myocardial fibrosis. Likewise, under
CC ischemia/reperfusion injury of NOL3-deficient mice have a markedly
CC increased myocardial infarct sizes (PubMed:16505176). Double homozygous
CC knockout mice for NOL3 and SGCD have an enhanced myofiber death and
CC subsequent dystrophic disease (PubMed:24312627).
CC {ECO:0000269|PubMed:16505176, ECO:0000269|PubMed:24312627}.
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DR EMBL; AK021023; BAB32281.1; -; mRNA.
DR CCDS; CCDS52657.1; -.
DR RefSeq; NP_084428.1; NM_030152.4.
DR RefSeq; XP_006531566.1; XM_006531503.2.
DR AlphaFoldDB; Q9D1X0; -.
DR SMR; Q9D1X0; -.
DR BioGRID; 219569; 3.
DR IntAct; Q9D1X0; 2.
DR STRING; 10090.ENSMUSP00000014920; -.
DR iPTMnet; Q9D1X0; -.
DR PhosphoSitePlus; Q9D1X0; -.
DR MaxQB; Q9D1X0; -.
DR PaxDb; Q9D1X0; -.
DR PRIDE; Q9D1X0; -.
DR ProteomicsDB; 252839; -.
DR Antibodypedia; 3976; 383 antibodies from 39 providers.
DR DNASU; 78688; -.
DR Ensembl; ENSMUST00000014920; ENSMUSP00000014920; ENSMUSG00000014776.
DR GeneID; 78688; -.
DR KEGG; mmu:78688; -.
DR UCSC; uc009ncd.1; mouse.
DR CTD; 8996; -.
DR MGI; MGI:1925938; Nol3.
DR VEuPathDB; HostDB:ENSMUSG00000014776; -.
DR eggNOG; ENOG502SR4M; Eukaryota.
DR GeneTree; ENSGT00510000049353; -.
DR HOGENOM; CLU_090015_0_0_1; -.
DR InParanoid; Q9D1X0; -.
DR OMA; RCAQQTV; -.
DR OrthoDB; 1488475at2759; -.
DR PhylomeDB; Q9D1X0; -.
DR TreeFam; TF336957; -.
DR BioGRID-ORCS; 78688; 5 hits in 74 CRISPR screens.
DR PRO; PR:Q9D1X0; -.
DR Proteomes; UP000000589; Chromosome 8.
DR RNAct; Q9D1X0; protein.
DR Bgee; ENSMUSG00000014776; Expressed in lumbar dorsal root ganglion and 136 other tissues.
DR ExpressionAtlas; Q9D1X0; baseline and differential.
DR Genevisible; Q9D1X0; MM.
DR GO; GO:0005737; C:cytoplasm; ISO:MGI.
DR GO; GO:0016020; C:membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IDA:MGI.
DR GO; GO:0005730; C:nucleolus; ISS:UniProtKB.
DR GO; GO:0016528; C:sarcoplasm; IDA:MGI.
DR GO; GO:0016529; C:sarcoplasmic reticulum; ISO:MGI.
DR GO; GO:0005509; F:calcium ion binding; ISO:MGI.
DR GO; GO:0089720; F:caspase binding; ISO:MGI.
DR GO; GO:0043027; F:cysteine-type endopeptidase inhibitor activity involved in apoptotic process; ISO:MGI.
DR GO; GO:0035877; F:death effector domain binding; IPI:UniProtKB.
DR GO; GO:0005123; F:death receptor binding; IPI:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0019900; F:kinase binding; ISO:MGI.
DR GO; GO:0019902; F:phosphatase binding; ISO:MGI.
DR GO; GO:0005102; F:signaling receptor binding; IPI:UniProtKB.
DR GO; GO:0001974; P:blood vessel remodeling; IMP:UniProtKB.
DR GO; GO:0010659; P:cardiac muscle cell apoptotic process; IMP:UniProtKB.
DR GO; GO:0071456; P:cellular response to hypoxia; ISO:MGI.
DR GO; GO:0097340; P:inhibition of cysteine-type endopeptidase activity; ISO:MGI.
DR GO; GO:1990001; P:inhibition of cysteine-type endopeptidase activity involved in apoptotic process; ISO:MGI.
DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; IMP:UniProtKB.
DR GO; GO:0006376; P:mRNA splice site selection; ISS:UniProtKB.
DR GO; GO:0045445; P:myoblast differentiation; ISO:MGI.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:0010667; P:negative regulation of cardiac muscle cell apoptotic process; IMP:UniProtKB.
DR GO; GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; ISO:MGI.
DR GO; GO:0051481; P:negative regulation of cytosolic calcium ion concentration; ISO:MGI.
DR GO; GO:1903073; P:negative regulation of death-inducing signaling complex assembly; ISO:MGI.
DR GO; GO:2001237; P:negative regulation of extrinsic apoptotic signaling pathway; ISO:MGI.
DR GO; GO:1902042; P:negative regulation of extrinsic apoptotic signaling pathway via death domain receptors; ISO:MGI.
DR GO; GO:1903206; P:negative regulation of hydrogen peroxide-induced cell death; ISO:MGI.
DR GO; GO:1903298; P:negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway; ISS:UniProtKB.
DR GO; GO:2001243; P:negative regulation of intrinsic apoptotic signaling pathway; ISO:MGI.
DR GO; GO:0051562; P:negative regulation of mitochondrial calcium ion concentration; ISO:MGI.
DR GO; GO:1902109; P:negative regulation of mitochondrial membrane permeability involved in apoptotic process; IMP:UniProtKB.
DR GO; GO:0014736; P:negative regulation of muscle atrophy; IMP:UniProtKB.
DR GO; GO:0060547; P:negative regulation of necrotic cell death; IMP:UniProtKB.
DR GO; GO:1902176; P:negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway; ISO:MGI.
DR GO; GO:1903215; P:negative regulation of protein targeting to mitochondrion; ISO:MGI.
DR GO; GO:0090201; P:negative regulation of release of cytochrome c from mitochondria; ISS:UniProtKB.
DR GO; GO:0010664; P:negative regulation of striated muscle cell apoptotic process; IMP:UniProtKB.
DR GO; GO:0010804; P:negative regulation of tumor necrosis factor-mediated signaling pathway; IMP:UniProtKB.
DR GO; GO:0051259; P:protein complex oligomerization; ISS:UniProtKB.
DR GO; GO:0010468; P:regulation of gene expression; IMP:MGI.
DR GO; GO:1901222; P:regulation of NIK/NF-kappaB signaling; IMP:UniProtKB.
DR GO; GO:0010880; P:regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum; ISO:MGI.
DR GO; GO:0014808; P:release of sequestered calcium ion into cytosol by sarcoplasmic reticulum; ISO:MGI.
DR GO; GO:0001666; P:response to hypoxia; IMP:MGI.
DR GO; GO:0014876; P:response to injury involved in regulation of muscle adaptation; IMP:MGI.
DR GO; GO:0002931; P:response to ischemia; IMP:UniProtKB.
DR GO; GO:0048659; P:smooth muscle cell proliferation; ISO:MGI.
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..220
FT /note="Nucleolar protein 3"
FT /id="PRO_0000144100"
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:0000250|UniProtKB:Q62881"
FT REGION 111..220
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 156..220
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 149
FT /note="Phosphothreonine; by CK2"
FT /evidence="ECO:0000250|UniProtKB:Q62881"
FT LIPID 2
FT /note="N-myristoyl glycine"
FT /evidence="ECO:0000250|UniProtKB:O60936"
FT MUTAGEN 31
FT /note="L->F: Unable to inhibit TNF-induced necrosis; when
FT associated with R-69. Unable to induce TNF nuclear
FT translocation; when associated with R-69."
FT /evidence="ECO:0000269|PubMed:24440909"
FT MUTAGEN 69
FT /note="G->R: Unable to inhibit TNF-induced necrosis; when
FT associated with F-31. Unable to induce TNF nuclear
FT translocation; when associated with F-31."
FT /evidence="ECO:0000269|PubMed:24440909"
SQ SEQUENCE 220 AA; 24568 MW; A4DCD57C1EB320A2 CRC64;
MGNVQERPSE TIDRERKRLV ETLQADSGLL LDALVARGVL TGPEYEALDA LPDAERRVRR
LLLLVQSKGE AACQELLRCA QQTVRMPDPA WDWQHVGPGY RNRSYDPSCP GHWTPEAPSS
GTTCPELPRA SEQEEVGGPE GSEALQPRTP EEPELEAEAT EGDEPDLEQE MNPEQEPEPE
PEPEPEPEPE PEPEPEPEPE PEPEPEPEPD FQEEDESEDS
