{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"Q9Y5A9","secondaryAccessions":["A6NKG4","A8K966","B4E1G7","D3DPM8","Q5VSZ9","Q8TDH0","Q9BUJ5"],"uniProtkbId":"YTHD2_HUMAN","entryAudit":{"firstPublicDate":"2003-02-12","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"2004-01-16","entryVersion":201,"sequenceVersion":2},"annotationScore":5.0,"organism":{"scientificName":"Homo sapiens","commonName":"Human","taxonId":9606,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Primates","Haplorrhini","Catarrhini","Hominidae","Homo"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"YTH domain-containing family protein 2"},"shortNames":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"31292544"},{"evidenceCode":"ECO:0000303","source":"PubMed","id":"32492408"}],"value":"DF2"}]},"alternativeNames":[{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"Reference","id":"Ref.3"}],"value":"CLL-associated antigen KW-14"}},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"Reference","id":"Ref.2"}],"value":"High-glucose-regulated protein 8"}},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"10508479"}],"value":"Renal carcinoma antigen NY-REN-2"}}]},"genes":[{"geneName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"24284625"},{"evidenceCode":"ECO:0000312","source":"HGNC","id":"HGNC:31675"}],"value":"YTHDF2"},"synonyms":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"Reference","id":"Ref.2"}],"value":"HGRG8"}]}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q91YT7"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"22575960"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24284625"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25412658"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25412661"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26046440"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26318451"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26458103"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"27558897"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28106072"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30065315"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30428350"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30559377"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30930054"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31292544"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31388144"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31642031"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31815440"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32169943"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32267835"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32451507"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32492408"}],"value":"Specifically recognizes and binds N6-methyladenosine (m6A)-containing RNAs, and regulates their stability (PubMed:24284625, PubMed:26046440, PubMed:26318451, PubMed:32492408). M6A is a modification present at internal sites of mRNAs and some non-coding RNAs and plays a role in mRNA stability and processing (PubMed:22575960, PubMed:24284625, PubMed:25412658, PubMed:25412661, PubMed:32492408). Acts as a regulator of mRNA stability by promoting degradation of m6A-containing mRNAs via interaction with the CCR4-NOT and ribonuclease P/MRP complexes, depending on the context (PubMed:24284625, PubMed:26046440, PubMed:27558897, PubMed:30930054, PubMed:32492408). The YTHDF paralogs (YTHDF1, YTHDF2 and YTHDF3) share m6A-containing mRNAs targets and act redundantly to mediate mRNA degradation and cellular differentiation (PubMed:28106072, PubMed:32492408). M6A-containing mRNAs containing a binding site for RIDA/HRSP12 (5'-GGUUC-3') are preferentially degraded by endoribonucleolytic cleavage: cooperative binding of RIDA/HRSP12 and YTHDF2 to transcripts leads to recruitment of the ribonuclease P/MRP complex (PubMed:30930054). Other m6A-containing mRNAs undergo deadenylation via direct interaction between YTHDF2 and CNOT1, leading to recruitment of the CCR4-NOT and subsequent deadenylation of m6A-containing mRNAs (PubMed:27558897). Required maternally to regulate oocyte maturation: probably acts by binding to m6A-containing mRNAs, thereby regulating maternal transcript dosage during oocyte maturation, which is essential for the competence of oocytes to sustain early zygotic development (By similarity). Also required during spermatogenesis: regulates spermagonial adhesion by promoting degradation of m6A-containing transcripts coding for matrix metallopeptidases (By similarity). Also involved in hematopoietic stem cells specification by binding to m6A-containing mRNAs, leading to promote their degradation (PubMed:30065315). Also acts as a regulator of neural development by promoting m6A-dependent degradation of neural development-related mRNA targets (By similarity). Inhibits neural specification of induced pluripotent stem cells by binding to methylated neural-specific mRNAs and promoting their degradation, thereby restraining neural differentiation (PubMed:32169943). Regulates circadian regulation of hepatic lipid metabolism: acts by promoting m6A-dependent degradation of PPARA transcripts (PubMed:30428350). Regulates the innate immune response to infection by inhibiting the type I interferon response: acts by binding to m6A-containing IFNB transcripts and promoting their degradation (PubMed:30559377). May also act as a promoter of cap-independent mRNA translation following heat shock stress: upon stress, relocalizes to the nucleus and specifically binds mRNAs with some m6A methylation mark at their 5'-UTR, protecting demethylation of mRNAs by FTO, thereby promoting cap-independent mRNA translation (PubMed:26458103). Regulates mitotic entry by promoting the phase-specific m6A-dependent degradation of WEE1 transcripts (PubMed:32267835). Promotes formation of phase-separated membraneless compartments, such as P-bodies or stress granules, by undergoing liquid-liquid phase separation upon binding to mRNAs containing multiple m6A-modified residues: polymethylated mRNAs act as a multivalent scaffold for the binding of YTHDF proteins, juxtaposing their disordered regions and thereby leading to phase separation (PubMed:31292544, PubMed:31388144, PubMed:31642031, PubMed:32451507). The resulting mRNA-YTHDF complexes then partition into different endogenous phase-separated membraneless compartments, such as P-bodies, stress granules or neuronal RNA granules (PubMed:31292544). May also recognize and bind RNAs modified by C5-methylcytosine (m5C) and act as a regulator of rRNA processing (PubMed:31815440)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29447282"}],"value":"(Microbial infection) Promotes viral gene expression and replication of polyomavirus SV40: acts by binding to N6-methyladenosine (m6A)-containing viral RNAs (PubMed:29447282)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29659627"}],"value":"(Microbial infection) Promotes viral gene expression and virion production of kaposis sarcoma-associated herpesvirus (KSHV) at some stage of the KSHV life cycle (in iSLK.219 and iSLK.BAC16 cells) (PubMed:29659627). Acts by binding to N6-methyladenosine (m6A)-containing viral RNAs (PubMed:29659627)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"27558897"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28106072"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30930054"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32492408"}],"value":"Interacts with CNOT1; interaction is direct and promotes recruitment of the CCR4-NOT complex (PubMed:27558897, PubMed:32492408). Interacts with YTHDF3 (PubMed:28106072). Interacts with RIDA/HRSP12; interaction leads to recruitment of the ribonuclease P/MRP complex (PubMed:30930054)"}],"commentType":"SUBUNIT"},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26458103"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31292544"}],"value":"Localizes to the cytosol and relocates to the nucleus following heat shock stress (PubMed:26458103). Can partition into different structures: into P-bodies in unstressed cells, and into stress granules during stress (PubMed:31292544)"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26458103"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31292544"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32492408"}],"value":"Cytoplasm, cytosol","id":"SL-0091"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24284625"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31292544"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32492408"}],"value":"Cytoplasm, P-body","id":"SL-0230"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31292544"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32451507"}],"value":"Cytoplasm, Stress granule","id":"SL-0496"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26458103"}],"value":"Nucleus","id":"SL-0191"}}]},{"commentType":"ALTERNATIVE PRODUCTS","events":["Alternative splicing"],"isoforms":[{"name":{"value":"1"},"isoformIds":["Q9Y5A9-1"],"isoformSequenceStatus":"Displayed"},{"name":{"value":"2"},"isoformIds":["Q9Y5A9-2"],"sequenceIds":["VSP_009297"],"isoformSequenceStatus":"Described"}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32169943"}],"value":"Highly expressed in induced pluripotent stem cells (iPSCs) and down-regulated during neural differentiation"}],"commentType":"TISSUE SPECIFICITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26458103"}],"value":"Following heat shock stress"}],"commentType":"INDUCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31292544"}],"value":"The disordered regions have the ability to interact with each other and to 'phase separate' into liquid droplets within the cytosol following binding to mRNAs containing multiple m6A-modified residues (PubMed:31292544). This leads to the partition of m6A-containing mRNAs into membraneless compartments, where mRNAs may be stored, degraded or used to transport mRNAs to dendritic arbors in neurons (PubMed:31292544)"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32267835"}],"value":"Ubiquitinated by the SCF(SKP2) complex, leading to its degradation"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Belongs to the YTHDF family. YTHDF2 subfamily"}],"commentType":"SIMILARITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29109479"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29447282"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29659627"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30559377"}],"value":"The role of YTHDF2 and N6-methyladenosine (m6A) in virus expression and replication is unclear (PubMed:29109479, PubMed:29447282, PubMed:29659627, PubMed:30559377). According to some reports, YTHDF2 promotes viral gene expression and replication of polyomavirus SV40 and herpesvirus (KSHV) by binding to N6-methyladenosine (m6A)-containing viral RNAs (PubMed:29447282, PubMed:29659627). Another report however suggests that YTHDF2 regulates virus expression and replication indirectly, via its ability to inhibit the type I interferon response, thereby promoting virus expression (PubMed:30559377). Indirect regulation via inhibition of type I interferon response might explain why contradictory results have been reported for its role in KSHV virus replication (PubMed:29109479, PubMed:29659627)"}],"commentType":"CAUTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26046440"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32492408"}],"value":"Previous studies suggested the 3 different paralogs (YTHDF1, YTHDF2 and YTHDF3) have unique functions with limited redundancy (PubMed:26046440). However, later studies showed that YTHDF1, YTHDF2 and YTHDF3 paralogs have redundant functions to a profound extent and directly promote degradation of m6A-containing mRNAs (PubMed:32492408)"}],"commentType":"CAUTION"},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Frameshift","sequence":"AAD42861.1","evidences":[{"evidenceCode":"ECO:0000305"}]},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Frameshift","sequence":"AAF08813.1","evidences":[{"evidenceCode":"ECO:0000305"}]},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Miscellaneous discrepancy","sequence":"AAL99921.1","evidences":[{"evidenceCode":"ECO:0000305"}]},{"commentType":"WEB RESOURCE","resourceName":"Protein Spotlight","resourceUrl":"https://www.proteinspotlight.org/back_issues/238/","ftp":false,"note":"On the benefits of disorder - Issue 238 of August 2021"}],"features":[{"type":"Initiator 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