{"results":[{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"Q8NEB9","secondaryAccessions":["Q15134"],"uniProtkbId":"PK3C3_HUMAN","entryAudit":{"firstPublicDate":"2005-12-06","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"2002-10-01","entryVersion":203,"sequenceVersion":1},"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":{"value":"Phosphatidylinositol 3-kinase catalytic subunit type 3"},"shortNames":[{"value":"PI3-kinase type 3"},{"value":"PI3K type 3"},{"value":"PtdIns-3-kinase type 3"}],"ecNumbers":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"7628435"}],"value":"2.7.1.137"}]},"alternativeNames":[{"fullName":{"value":"Phosphatidylinositol 3-kinase p100 subunit"}},{"fullName":{"value":"Phosphoinositide-3-kinase class 3"}},{"fullName":{"value":"hVps34"}}]},"genes":[{"geneName":{"evidences":[{"evidenceCode":"ECO:0000312","source":"HGNC","id":"HGNC:8974"}],"value":"PIK3C3"},"synonyms":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"VPS34"}]}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"O88763"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"14617358"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20208530"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20643123"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32690950"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33637724"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33993848"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"7628435"}],"value":"Catalytic subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate; different complex forms are believed to play a role in multiple membrane trafficking pathways: PI3KC3-C1 is involved in initiation of autophagosomes and PI3KC3-C2 in maturation of autophagosomes and endocytosis (PubMed:14617358, PubMed:33637724, PubMed:7628435, PubMed:33993848). As part of PI3KC3-C1, promotes endoplasmic reticulum membrane curvature formation prior to vesicle budding (PubMed:32690950). Involved in regulation of degradative endocytic trafficking and required for the abscission step in cytokinesis, probably in the context of PI3KC3-C2 (PubMed:20208530, PubMed:20643123). Involved in the transport of lysosomal enzyme precursors to lysosomes (By similarity). Required for transport from early to late endosomes (By similarity)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"34320401"}],"value":"(Microbial infection) Kinase activity is required for SARS coronavirus-2/SARS-CoV-2 replication"}],"commentType":"FUNCTION"},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate) + ADP + H(+)","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:12709"},{"database":"ChEBI","id":"CHEBI:15378"},{"database":"ChEBI","id":"CHEBI:30616"},{"database":"ChEBI","id":"CHEBI:57880"},{"database":"ChEBI","id":"CHEBI:58088"},{"database":"ChEBI","id":"CHEBI:456216"}],"ecNumber":"2.7.1.137","evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"7628435"}]},"physiologicalReactions":[{"directionType":"left-to-right","reactionCrossReference":{"database":"Rhea","id":"RHEA:12710"},"evidences":[{"evidenceCode":"ECO:0000305","source":"PubMed","id":"7628435"}]}]},{"commentType":"COFACTOR","cofactors":[{"name":"Mn(2+)","evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"7628435"}],"cofactorCrossReference":{"database":"ChEBI","id":"CHEBI:29035"}}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q6PF93"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q9TXI7"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"14617358"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"16417406"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19050071"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19270696"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20643123"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"22493499"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23878393"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23954414"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25490155"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31806350"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32690950"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33473107"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33993848"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"7628435"},{"evidenceCode":"ECO:0000305"}],"value":"Component of the PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex the core of which is composed of the catalytic subunit PIK3C3, the regulatory subunit PIK3R4 and BECN1 associating with additional regulatory/auxiliary subunits to form alternative complex forms. Alternative complex forms containing a fourth regulatory subunit in a mutually exclusive manner are: the PI3K complex I (PI3KC3-C1) containing ATG14, and the PI3K complex II (PI3KC3-C2) containing UVRAG. PI3KC3-C1 displays a V-shaped architecture with PIK3R4 serving as a bridge between PIK3C3 and the ATG14:BECN1 subcomplex. Both, PI3KC3-C1 and PI3KC3-C2, can associate with further regulatory subunits such as RUBCN, SH3GLB1/Bif-1 and AMBRA1 (PubMed:19050071, PubMed:19270696, PubMed:20643123, PubMed:23878393, PubMed:25490155, PubMed:7628435). PI3KC3-C1 probably associates with PIK3CB (By similarity). Interacts with RAB7A in the presence of PIK3R4 (PubMed:14617358). Interacts with AMBRA1 (By similarity). Interacts with BECN1P1/BECN2 (PubMed:23954414). Interacts with SLAMF1 (PubMed:22493499). May be a component of a complex composed of RAB5A (in GDP-bound form), DYN2 and PIK3C3 (By similarity). Interacts with NCKAP1L (PubMed:16417406). Interacts with ATG14; this interaction is increased in the absence of TMEM39A (PubMed:31806350). Interacts with STEEP1; the interaction is STING1-dependent and required for trafficking of STING1 from the endoplasmic reticulum (PubMed:32690950). Interacts with YWHAG (PubMed:33473107). Interacts with ARMC3 (By similarity). Interacts with AHCYL1; the interaction is strongly enhanced by SAH in a dose-dependent manner (PubMed:33993848)"}],"commentType":"SUBUNIT"},{"commentType":"INTERACTION","interactions":[{"interactantOne":{"uniProtKBAccession":"Q8NEB9","intActId":"EBI-1056470"},"interactantTwo":{"uniProtKBAccession":"Q6ZNE5","geneName":"ATG14","intActId":"EBI-2690371"},"numberOfExperiments":30,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q8NEB9","intActId":"EBI-1056470"},"interactantTwo":{"uniProtKBAccession":"Q14457","geneName":"BECN1","intActId":"EBI-949378"},"numberOfExperiments":43,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q8NEB9","intActId":"EBI-1056470"},"interactantTwo":{"uniProtKBAccession":"Q96F24","geneName":"NRBF2","intActId":"EBI-2362014"},"numberOfExperiments":14,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q8NEB9","intActId":"EBI-1056470"},"interactantTwo":{"uniProtKBAccession":"Q92622","geneName":"RUBCN","intActId":"EBI-2952709"},"numberOfExperiments":9,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q8NEB9","intActId":"EBI-1056470"},"interactantTwo":{"uniProtKBAccession":"Q9P2Y5","geneName":"UVRAG","intActId":"EBI-2952704"},"numberOfExperiments":25,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q8NEB9","intActId":"EBI-1056470"},"interactantTwo":{"uniProtKBAccession":"Q17UT5","geneName":"X","intActId":"EBI-15834514"},"numberOfExperiments":2,"organismDiffer":true}]},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q6PF93"},{"evidenceCode":"ECO:0000305","source":"PubMed","id":"14617358"}],"value":"As component of the PI3K complex I localized to pre-autophagosome structures. As component of the PI3K complex II localized predominantly to endosomes (PubMed:14617358). Also localizes to discrete punctae along the ciliary axoneme and to the base of the ciliary axoneme (By similarity)"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20208530"}],"value":"Midbody","id":"SL-0469"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"14617358"}],"value":"Late endosome","id":"SL-0152"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000305","source":"PubMed","id":"14617358"}],"value":"Cytoplasmic vesicle, autophagosome","id":"SL-0023"}}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"7628435"}],"value":"Ubiquitously expressed, with a highest expression in skeletal muscle"}],"commentType":"TISSUE SPECIFICITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33637724"}],"value":"Ubiquitinated via 'Lys-29'- and 'Lys-48'-linked ubiquitination by UBE3C, promoting its degradation (PubMed:33637724). Deubiquitination by ZRANB1/TRABID promotes its stabilization, leading to autophagosome maturation (PubMed:33637724)"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU00880"}],"value":"Belongs to the PI3/PI4-kinase family"}],"commentType":"SIMILARITY"}],"features":[{"type":"Chain","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":887,"modifier":"EXACT"}},"description":"Phosphatidylinositol 3-kinase catalytic subunit type 3","featureId":"PRO_0000088802"},{"type":"Domain","location":{"start":{"value":35,"modifier":"EXACT"},"end":{"value":184,"modifier":"EXACT"}},"description":"C2 PI3K-type","evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU00880"}]},{"type":"Domain","location":{"start":{"value":283,"modifier":"EXACT"},"end":{"value":520,"modifier":"EXACT"}},"description":"PIK 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