YTHD3_MOUSE
ID YTHD3_MOUSE Reviewed; 585 AA.
AC Q8BYK6; Q3UVI5; Q6NXJ6; Q6NXJ8; Q8BKB6;
DT 04-APR-2006, integrated into UniProtKB/Swiss-Prot.
DT 04-APR-2006, sequence version 2.
DT 03-AUG-2022, entry version 119.
DE RecName: Full=YTH domain-containing family protein 3 {ECO:0000305};
GN Name=Ythdf3 {ECO:0000303|PubMed:30591559, ECO:0000312|MGI:MGI:1918850};
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] (ISOFORMS 2 AND 3).
RC STRAIN=C57BL/6J; TISSUE=Eye, Hypothalamus, and Urinary bladder;
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 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC STRAIN=C57BL/6J, and NMRI; TISSUE=Brain, and Mammary tumor;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP PROTEIN SEQUENCE OF 196-206, AND IDENTIFICATION BY MASS SPECTROMETRY.
RC STRAIN=OF1; TISSUE=Hippocampus;
RA Lubec G., Sunyer B., Chen W.-Q.;
RL Submitted (JAN-2009) to UniProtKB.
RN [4]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Kidney, Liver, 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, AND DISRUPTION PHENOTYPE.
RX PubMed=30591559; DOI=10.1073/pnas.1812536116;
RA Zhang Y., Wang X., Zhang X., Wang J., Ma Y., Zhang L., Cao X.;
RT "RNA-binding protein YTHDF3 suppresses interferon-dependent antiviral
RT responses by promoting FOXO3 translation.";
RL Proc. Natl. Acad. Sci. U.S.A. 116:976-981(2019).
RN [6]
RP FUNCTION, AND INTERACTION WITH PAN3.
RX PubMed=32905781; DOI=10.1016/j.celrep.2020.108120;
RA Liu J., Gao M., Xu S., Chen Y., Wu K., Liu H., Wang J., Yang X., Wang J.,
RA Liu W., Bao X., Chen J.;
RT "YTHDF2/3 are required for somatic reprogramming through different RNA
RT deadenylation pathways.";
RL Cell Rep. 32:108120-108120(2020).
RN [7]
RP FUNCTION, SUBCELLULAR LOCATION, AND DISRUPTION PHENOTYPE.
RX PubMed=32943573; DOI=10.1101/gad.340695.120;
RA Lasman L., Krupalnik V., Viukov S., Mor N., Aguilera-Castrejon A.,
RA Schneir D., Bayerl J., Mizrahi O., Peles S., Tawil S., Sathe S.,
RA Nachshon A., Shani T., Zerbib M., Kilimnik I., Aigner S., Shankar A.,
RA Mueller J.R., Schwartz S., Stern-Ginossar N., Yeo G.W., Geula S.,
RA Novershtern N., Hanna J.H.;
RT "Context-dependent functional compensation between Ythdf m6A reader
RT proteins.";
RL Genes Dev. 34:1373-1391(2020).
CC -!- FUNCTION: Specifically recognizes and binds N6-methyladenosine (m6A)-
CC containing RNAs, and regulates their stability (PubMed:32905781,
CC PubMed:32943573). M6A is a modification present at internal sites of
CC mRNAs and some non-coding RNAs and plays a role in mRNA stability and
CC processing (PubMed:32943573). Acts as a regulator of mRNA stability by
CC promoting degradation of m6A-containing mRNAs via interaction with the
CC CCR4-NOT complex or PAN3 (PubMed:32943573, PubMed:32905781). The YTHDF
CC paralogs (YTHDF1, YTHDF2 and YTHDF3) share m6A-containing mRNAs targets
CC and act redundantly to mediate mRNA degradation and cellular
CC differentiation (PubMed:32943573). Acts as a negative regulator of type
CC I interferon response by down-regulating interferon-stimulated genes
CC (ISGs) expression: acts by binding to FOXO3 mRNAs (PubMed:30591559).
CC Binds to FOXO3 mRNAs independently of METTL3-mediated m6A modification
CC (PubMed:30591559). Can also act as a regulator of mRNA stability in
CC cooperation with YTHDF2 by binding to m6A-containing mRNA and promoting
CC their degradation (By similarity). Recognizes and binds m6A-containing
CC circular RNAs (circRNAs); circRNAs are generated through back-splicing
CC of pre-mRNAs, a non-canonical splicing process promoted by dsRNA
CC structures across circularizing exons (By similarity). Promotes
CC formation of phase-separated membraneless compartments, such as P-
CC bodies or stress granules, by undergoing liquid-liquid phase separation
CC upon binding to mRNAs containing multiple m6A-modified residues:
CC polymethylated mRNAs act as a multivalent scaffold for the binding of
CC YTHDF proteins, juxtaposing their disordered regions and thereby
CC leading to phase separation (By similarity). The resulting mRNA-YTHDF
CC complexes then partition into different endogenous phase-separated
CC membraneless compartments, such as P-bodies, stress granules or
CC neuronal RNA granules (By similarity). May also recognize and bind N1-
CC methyladenosine (m1A)-containing mRNAs: inhibits trophoblast invasion
CC by binding to m1A-methylated transcripts of IGF1R, promoting their
CC degradation (By similarity). {ECO:0000250|UniProtKB:Q7Z739,
CC ECO:0000269|PubMed:30591559, ECO:0000269|PubMed:32905781,
CC ECO:0000269|PubMed:32943573}.
CC -!- SUBUNIT: Interacts with CNOT1; promoting recruitment of the CCR4-NOT
CC complex (By similarity). Interacts with YTHDF1 (By similarity).
CC Interacts with YTHDF2 (By similarity). Interacts with PAN3
CC (PubMed:32905781). {ECO:0000250|UniProtKB:Q7Z739,
CC ECO:0000269|PubMed:32905781}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000305|PubMed:32943573}.
CC Cytoplasm, P-body {ECO:0000250|UniProtKB:Q7Z739}. Cytoplasm, Stress
CC granule {ECO:0000250|UniProtKB:Q7Z739}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q8BYK6-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8BYK6-2; Sequence=VSP_017833;
CC Name=3;
CC IsoId=Q8BYK6-3; Sequence=VSP_017834;
CC -!- DOMAIN: The disordered regions have the ability to interact with each
CC other and to 'phase separate' into liquid droplets within the cytosol
CC following binding to mRNAs containing multiple m6A-modified residues.
CC This leads to the partition of m6A-containing mRNAs into membraneless
CC compartments, where mRNAs may be stored, degraded or used to transport
CC mRNAs to dendritic arbors in neurons. {ECO:0000250|UniProtKB:Q7Z739}.
CC -!- DISRUPTION PHENOTYPE: Mice are viable and normal in size but display
CC increased interferon-stimulated genes (ISGs) levels and are resistant
CC to several viral infections (PubMed:30591559). Mice lacking Ythdf1,
CC Ythdf2 and Ythdf3 display early embryonic lethality and show defects in
CC embryonic stem cell differentiation (PubMed:32943573).
CC {ECO:0000269|PubMed:30591559, ECO:0000269|PubMed:32943573}.
CC -!- SIMILARITY: Belongs to the YTHDF family. YTHDF3 subfamily.
CC {ECO:0000305}.
CC -!- CAUTION: Was initially reported to act as a regulator of mRNA
CC translation efficiency by binding to m6A-containing mRNAs
CC (PubMed:30591559). This study suggested that the 3 different paralogs
CC (YTHDF1, YTHDF2 and YTHDF3) have unique functions with limited
CC redundancy (PubMed:32943573). However, later studies showed that
CC YTHDF1, YTHDF2 and YTHDF3 paralogs have redundant functions to a
CC profound extent and directly promote degradation of m6A-containing
CC mRNAs (PubMed:32943573). The effect on translation efficiency observed
CC earlier is probably indirect (PubMed:32943573).
CC {ECO:0000269|PubMed:30591559, ECO:0000269|PubMed:32943573}.
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DR EMBL; AK137245; BAE23284.1; -; mRNA.
DR EMBL; AK039176; BAC30267.1; -; mRNA.
DR EMBL; AK053736; BAC35498.1; -; mRNA.
DR EMBL; BC057158; AAH57158.1; -; mRNA.
DR EMBL; BC067040; AAH67040.1; -; mRNA.
DR EMBL; BC067042; AAH67042.1; -; mRNA.
DR CCDS; CCDS38396.1; -. [Q8BYK6-3]
DR CCDS; CCDS50869.1; -. [Q8BYK6-1]
DR CCDS; CCDS89615.1; -. [Q8BYK6-2]
DR RefSeq; NP_001139391.1; NM_001145919.1. [Q8BYK6-1]
DR RefSeq; NP_766265.3; NM_172677.3. [Q8BYK6-3]
DR AlphaFoldDB; Q8BYK6; -.
DR SMR; Q8BYK6; -.
DR BioGRID; 230816; 5.
DR STRING; 10090.ENSMUSP00000103983; -.
DR iPTMnet; Q8BYK6; -.
DR PhosphoSitePlus; Q8BYK6; -.
DR EPD; Q8BYK6; -.
DR MaxQB; Q8BYK6; -.
DR PaxDb; Q8BYK6; -.
DR PeptideAtlas; Q8BYK6; -.
DR PRIDE; Q8BYK6; -.
DR ProteomicsDB; 275050; -. [Q8BYK6-1]
DR ProteomicsDB; 275051; -. [Q8BYK6-2]
DR ProteomicsDB; 275052; -. [Q8BYK6-3]
DR Antibodypedia; 24763; 145 antibodies from 22 providers.
DR DNASU; 229096; -.
DR Ensembl; ENSMUST00000108345; ENSMUSP00000103982; ENSMUSG00000047213. [Q8BYK6-1]
DR Ensembl; ENSMUST00000108346; ENSMUSP00000103983; ENSMUSG00000047213. [Q8BYK6-3]
DR Ensembl; ENSMUST00000191774; ENSMUSP00000141610; ENSMUSG00000047213. [Q8BYK6-2]
DR GeneID; 229096; -.
DR KEGG; mmu:229096; -.
DR UCSC; uc008org.3; mouse. [Q8BYK6-3]
DR UCSC; uc008orh.3; mouse. [Q8BYK6-2]
DR UCSC; uc008ori.3; mouse. [Q8BYK6-1]
DR CTD; 253943; -.
DR MGI; MGI:1918850; Ythdf3.
DR VEuPathDB; HostDB:ENSMUSG00000047213; -.
DR eggNOG; KOG1901; Eukaryota.
DR GeneTree; ENSGT00940000158777; -.
DR HOGENOM; CLU_022715_1_1_1; -.
DR InParanoid; Q8BYK6; -.
DR OMA; GAYRSMG; -.
DR OrthoDB; 1523251at2759; -.
DR PhylomeDB; Q8BYK6; -.
DR TreeFam; TF323736; -.
DR BioGRID-ORCS; 229096; 6 hits in 72 CRISPR screens.
DR ChiTaRS; Ythdf3; mouse.
DR PRO; PR:Q8BYK6; -.
DR Proteomes; UP000000589; Chromosome 3.
DR RNAct; Q8BYK6; protein.
DR Bgee; ENSMUSG00000047213; Expressed in indifferent gonad and 256 other tissues.
DR Genevisible; Q8BYK6; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0010494; C:cytoplasmic stress granule; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0000932; C:P-body; ISS:UniProtKB.
DR GO; GO:0003729; F:mRNA binding; IBA:GO_Central.
DR GO; GO:1990247; F:N6-methyladenosine-containing RNA binding; ISS:UniProtKB.
DR GO; GO:0043022; F:ribosome binding; ISS:UniProtKB.
DR GO; GO:0003723; F:RNA binding; ISO:MGI.
DR GO; GO:0061157; P:mRNA destabilization; IMP:UniProtKB.
DR GO; GO:0060339; P:negative regulation of type I interferon-mediated signaling pathway; IMP:UniProtKB.
DR GO; GO:0070925; P:organelle assembly; ISS:UniProtKB.
DR GO; GO:0045727; P:positive regulation of translation; ISS:UniProtKB.
DR GO; GO:0043488; P:regulation of mRNA stability; IMP:UniProtKB.
DR GO; GO:1901163; P:regulation of trophoblast cell migration; ISS:UniProtKB.
DR GO; GO:0034063; P:stress granule assembly; ISS:UniProtKB.
DR InterPro; IPR007275; YTH_domain.
DR InterPro; IPR045168; YTH_prot.
DR PANTHER; PTHR12357; PTHR12357; 1.
DR Pfam; PF04146; YTH; 1.
DR PROSITE; PS50882; YTH; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Cytoplasm; Direct protein sequencing;
KW Phosphoprotein; Reference proteome; RNA-binding.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:Q7Z739"
FT CHAIN 2..585
FT /note="YTH domain-containing family protein 3"
FT /id="PRO_0000230992"
FT DOMAIN 416..550
FT /note="YTH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00225"
FT REGION 1..51
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 244..277
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 304..350
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1..26
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 36..51
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 304..333
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 334..350
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 422..424
FT /ligand="RNA"
FT /ligand_id="ChEBI:CHEBI:33697"
FT /ligand_part="N(6)-methyladenosine 5'-phosphate residue"
FT /ligand_part_id="ChEBI:CHEBI:74449"
FT /evidence="ECO:0000250|UniProtKB:Q7Z739"
FT BINDING 428
FT /ligand="RNA"
FT /ligand_id="ChEBI:CHEBI:33697"
FT /ligand_part="N(6)-methyladenosine 5'-phosphate residue"
FT /ligand_part_id="ChEBI:CHEBI:74449"
FT /evidence="ECO:0000250|UniProtKB:Q9Y5A9"
FT BINDING 438..439
FT /ligand="RNA"
FT /ligand_id="ChEBI:CHEBI:33697"
FT /ligand_part="N(6)-methyladenosine 5'-phosphate residue"
FT /ligand_part_id="ChEBI:CHEBI:74449"
FT /evidence="ECO:0000250|UniProtKB:Q7Z739"
FT BINDING 468
FT /ligand="RNA"
FT /ligand_id="ChEBI:CHEBI:33697"
FT /ligand_part="N(6)-methyladenosine 5'-phosphate residue"
FT /ligand_part_id="ChEBI:CHEBI:74449"
FT /evidence="ECO:0000250|UniProtKB:Q9Y5A9"
FT BINDING 492
FT /ligand="RNA"
FT /ligand_id="ChEBI:CHEBI:33697"
FT /ligand_part="N(6)-methyladenosine 5'-phosphate residue"
FT /ligand_part_id="ChEBI:CHEBI:74449"
FT /evidence="ECO:0000250|UniProtKB:Q7Z739"
FT BINDING 497
FT /ligand="RNA"
FT /ligand_id="ChEBI:CHEBI:33697"
FT /ligand_part="N(6)-methyladenosine 5'-phosphate residue"
FT /ligand_part_id="ChEBI:CHEBI:74449"
FT /evidence="ECO:0000250|UniProtKB:Q7Z739"
FT MOD_RES 2
FT /note="N-acetylserine"
FT /evidence="ECO:0000250|UniProtKB:Q7Z739"
FT MOD_RES 23
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q7Z739"
FT VAR_SEQ 1..17
FT /note="MSATSVDQRPKGQGNKV -> MFYLDLTLLHRATEETGEESF (in
FT isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:16141072"
FT /id="VSP_017833"
FT VAR_SEQ 45
FT /note="Q -> QKYRRAKQLFHC (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_017834"
FT CONFLICT 231
FT /note="A -> P (in Ref. 2; AAH67042)"
FT /evidence="ECO:0000305"
FT CONFLICT 502
FT /note="E -> G (in Ref. 1; BAC30267)"
FT /evidence="ECO:0000305"
FT CONFLICT 531
FT /note="N -> D (in Ref. 1; BAE23284)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 585 AA; 63961 MW; E6A12F76A3781770 CRC64;
MSATSVDQRP KGQGNKVSVQ NGSIHQKDAV NDDDFEPYLS SQTNQNNSYP PMSDPYMPSY
YAPSIGFPYS LGEAAWSTAG DQPMPYLTTY GQMSNGEHHY IPDGVFSQPG ALGNTPPFLG
QHGFNFFPGN ADFSTWGTSG SQGQSTQNSA YSSSYGYPPS SLGRAITDGQ AGFGNDTLSK
VPGISSIEQG MTGLKIGGDL TAAVTKTVGT ALSSSGMTSI ATNNVPPVSS AAPKPTSWAA
IARKPAKPQP KLKPKGNVGI GGSAVPPPPI KHNMNIGTWD EKGSVVKAPP TQPVLPPQTI
IQQPQPLIQP PPLVQSQLPQ QQPQPPQPQQ QQGPQPQAQP HQVQSQQPQL QNRWVAPRNR
GTGFNQNNGT GSENFGLGVV PVSASPSSVE VHPVLEKLKA INNYNPKDFD WNLKNGRVFI
IKSYSEDDIH RSIKYSIWCS TEHGNKRLDA AYRSLNGKGP LYLLFSVNGS GHFCGVAEMK
SVVDYNAYAG VWSQDKWKGK FEVKWIFVKD VPNNQLRHIR LENNDNKPVT NSRDTQEVPL
EKAKQVLKII ATFKHTTSIF DDFAHYEKRQ EEEEAMRRER NRNKQ
