ID LITAF_MOUSE Reviewed; 161 AA. AC Q9JLJ0; Q9EQI0; DT 06-DEC-2005, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-2000, sequence version 1. DT 24-JAN-2024, entry version 149. DE RecName: Full=Lipopolysaccharide-induced tumor necrosis factor-alpha factor homolog; DE Short=LPS-induced TNF-alpha factor homolog; DE AltName: Full=Estrogen-enhanced transcript protein {ECO:0000303|PubMed:12355436}; DE Short=mEET {ECO:0000303|PubMed:12355436}; DE AltName: Full=LITAF-like protein; DE AltName: Full=NEDD4 WW domain-binding protein 3; GN Name=Litaf; Synonyms=N4wbp3, Tbx1; 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 [MRNA], FUNCTION, TISSUE SPECIFICITY, INDUCTION, AND RP SUBCELLULAR LOCATION. RC TISSUE=Thymus; RX PubMed=12355436; RX DOI=10.1002/1521-4141(2002010)32:10<2837::aid-immu2837>3.0.co;2-v; RA Xie L.-P., Fu W.-X., Jin C., Dong X.-Y., Chen W.-F.; RT "Negative regulation of monocyte chemoattractant protein-1 gene expression RT by a mouse estrogen-enhanced transcript."; RL Eur. J. Immunol. 32:2837-2846(2002). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY, INDUCTION, AND RP DEVELOPMENTAL STAGE. RC TISSUE=Heart; RX PubMed=15025820; DOI=10.1179/096805104225003780; RA Bolcato-Bellemin A.-L., Mattei M.-G., Fenton M., Amar S.; RT "Molecular cloning and characterization of mouse LITAF cDNA: role in the RT regulation of tumor necrosis factor-alpha (TNF-alpha) gene expression."; RL J. Endotoxin Res. 10:15-23(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=C57BL/6J; TISSUE=Bone marrow, Colon, and Head; 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 [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=FVB/N; TISSUE=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 [5] RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-130, INTERACTION WITH NEDD4, MUTAGENESIS OF RP TYR-23 AND TYR-61, AND DOMAIN. RC TISSUE=Embryo; RX PubMed=11042109; DOI=10.1042/bj3510557; RA Jolliffe C.N., Harvey K.F., Haines B.P., Parasivam G., Kumar S.; RT "Identification of multiple proteins expressed in murine embryos as binding RT partners for the WW domains of the ubiquitin-protein ligase Nedd4."; RL Biochem. J. 351:557-565(2000). RN [6] RP FUNCTION, INTERACTION WITH STAT6, AND INDUCTION BY LIPOPOLYSACCHARIDE. RX PubMed=15793005; DOI=10.1073/pnas.0501159102; RA Tang X., Marciano D.L., Leeman S.E., Amar S.; RT "LPS induces the interaction of a transcription factor, LPS-induced TNF- RT alpha factor, and STAT6(B) with effects on multiple cytokines."; RL Proc. Natl. Acad. Sci. U.S.A. 102:5132-5137(2005). RN [7] RP FUNCTION. RX PubMed=16954198; DOI=10.1073/pnas.0605988103; RA Tang X., Metzger D., Leeman S., Amar S.; RT "LPS-induced TNF-alpha factor (LITAF)-deficient mice express reduced LPS- RT induced cytokine: Evidence for LITAF-dependent LPS signaling pathways."; RL Proc. Natl. Acad. Sci. U.S.A. 103:13777-13782(2006). RN [8] RP FUNCTION. RX PubMed=21980379; DOI=10.1371/journal.pone.0025083; RA Tang X., Yang Y., Amar S.; RT "Novel regulation of CCL2 gene expression by murine LITAF and STAT6B."; RL PLoS ONE 6:E25083-E25083(2011). RN [9] RP FUNCTION, DISRUPTION PHENOTYPE, AND TISSUE SPECIFICITY. RX PubMed=22160695; DOI=10.1073/pnas.1111492108; RA Merrill J.C., You J., Constable C., Leeman S.E., Amar S.; RT "Whole-body deletion of LPS-induced TNF-alpha factor (LITAF) markedly RT improves experimental endotoxic shock and inflammatory arthritis."; RL Proc. Natl. Acad. Sci. U.S.A. 108:21247-21252(2011). RN [10] RP FUNCTION, DISRUPTION PHENOTYPE, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, RP AND DEVELOPMENTAL STAGE. RX PubMed=22729949; DOI=10.1002/glia.22371; RA Somandin C., Gerber D., Pereira J.A., Horn M., Suter U.; RT "LITAF (SIMPLE) regulates Wallerian degeneration after injury but is not RT essential for peripheral nerve development and maintenance: implications RT for Charcot-Marie-Tooth disease."; RL Glia 60:1518-1528(2012). RN [11] RP FUNCTION. RX PubMed=23166352; DOI=10.1083/jcb.201204137; RA Lee S.M., Chin L.S., Li L.; RT "Charcot-Marie-Tooth disease-linked protein SIMPLE functions with the ESCRT RT machinery in endosomal trafficking."; RL J. Cell Biol. 199:799-816(2012). CC -!- FUNCTION: Plays a role in endosomal protein trafficking and in CC targeting proteins for lysosomal degradation. Plays a role in targeting CC endocytosed EGFR and ERGG3 for lysosomal degradation, and thereby helps CC down-regulate downstream signaling cascades (PubMed:23166352). Helps CC recruit the ESCRT complex components TSG101, HGS and STAM to CC cytoplasmic membranes. Probably plays a role in regulating protein CC degradation via its interaction with NEDD4 (By similarity). May also CC contribute to the regulation of gene expression in the nucleus. Binds CC DNA (in vitro) and may play a synergistic role with STAT6 in the CC nucleus in regulating the expression of various cytokines CC (PubMed:15793005, PubMed:21980379). May regulate the expression of CC numerous cytokines, such as TNF, CCL2, CCL5, CXCL1, IL1A and IL10 CC (PubMed:12355436, PubMed:15025820, PubMed:16954198, PubMed:21980379, CC PubMed:22160695). {ECO:0000250|UniProtKB:Q99732, CC ECO:0000269|PubMed:12355436, ECO:0000269|PubMed:15025820, CC ECO:0000269|PubMed:15793005, ECO:0000269|PubMed:16954198, CC ECO:0000269|PubMed:21980379, ECO:0000269|PubMed:23166352}. CC -!- SUBUNIT: Monomer. Interacts with NEDD4 (PubMed:11042109). Interacts CC (via PSAP motif) with TSG101, a component of the ESCRT-I complex CC (endosomal sorting complex required for transport I). Interacts with CC WWOX. Interacts with STAM, a component of the ESCRT-0 complex; the CC interaction is direct. Identified in a complex with STAM and HGS; CC within this complex, interacts directly with STAM, but not with HGS. CC Interacts with STAT6 (PubMed:15793005). {ECO:0000250|UniProtKB:Q99732, CC ECO:0000269|PubMed:11042109, ECO:0000269|PubMed:15793005}. CC -!- INTERACTION: CC Q9JLJ0; P46935: Nedd4; NbExp=5; IntAct=EBI-643664, EBI-773516; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q99732}. Nucleus CC {ECO:0000250|UniProtKB:Q99732}. Lysosome membrane CC {ECO:0000250|UniProtKB:Q99732}; Peripheral membrane protein CC {ECO:0000250|UniProtKB:Q99732}; Cytoplasmic side CC {ECO:0000250|UniProtKB:Q99732}. Early endosome membrane CC {ECO:0000250|UniProtKB:Q99732}. Late endosome membrane CC {ECO:0000250|UniProtKB:Q99732}. Endosome membrane CC {ECO:0000250|UniProtKB:Q99732}; Peripheral membrane protein CC {ECO:0000250|UniProtKB:Q99732}; Cytoplasmic side CC {ECO:0000250|UniProtKB:Q99732}. Cell membrane CC {ECO:0000250|UniProtKB:Q99732}; Peripheral membrane protein CC {ECO:0000250|UniProtKB:Q99732}; Cytoplasmic side CC {ECO:0000250|UniProtKB:Q99732}. Golgi apparatus membrane CC {ECO:0000250|UniProtKB:Q99732}. Note=Associated with membranes of CC lysosomes, early and late endosomes. Can translocate from the cytoplasm CC into the nucleus (By similarity). Detected at Schmidt-Lanterman CC incisures and in nodal regions of myelinating Schwann cells CC (PubMed:22729949). {ECO:0000250|UniProtKB:Q99732, CC ECO:0000269|PubMed:22729949}. CC -!- TISSUE SPECIFICITY: Detected in brain, heart, lung, liver, spleen and CC bone marrow (PubMed:22160695). Detected in myelinating Schwann cells in CC sciatic nerve and in bone marrow-derived macrophages (at protein level) CC (PubMed:22729949). Widely expressed. Highly expressed in liver. CC {ECO:0000269|PubMed:12355436, ECO:0000269|PubMed:15025820, CC ECO:0000269|PubMed:22160695, ECO:0000269|PubMed:22729949}. CC -!- DEVELOPMENTAL STAGE: Expression in sciatic nerve is low in neonates, CC culminates seven days after birth and decreases rapidly thereafter (at CC protein level) (PubMed:22729949). Strong expression is detected at E.7 CC and drops at 11 dpc. {ECO:0000269|PubMed:15025820, CC ECO:0000269|PubMed:22729949}. CC -!- INDUCTION: Up-regulated in macrophages exposed to lipopolysaccharide CC (LPS) (at protein level) (PubMed:15793005). By estrogen and CC lipopolysaccharides (LPS). {ECO:0000269|PubMed:12355436, CC ECO:0000269|PubMed:15025820, ECO:0000269|PubMed:15793005}. CC -!- DOMAIN: The PPxY motif mediates interaction with WWOX and NEDD4. CC {ECO:0000250|UniProtKB:Q99732}. CC -!- DOMAIN: The LITAF domain is stabilized by a bound zinc ion. The LITAF CC domain contains an amphipathic helix that mediates interaction with CC lipid membranes. It interacts specifically with CC phosphatidylethanolamine lipid headgroups, but not with CC phosphoglycerol, phosphocholine, phosphoserine or CC inositolhexakisphosphate. {ECO:0000250|UniProtKB:Q99732}. CC -!- PTM: Phosphorylated on tyrosine residues in response to EGF. CC {ECO:0000250|UniProtKB:Q99732}. CC -!- DISRUPTION PHENOTYPE: No visible phenotype. Mice are born at the CC expected Mendelian rate and are fertile. Mutant mice display altered CC responses to nerve crush injury, with higher numbers of macrophages in CC injured nerves five days after nerve crush injury, but at later time CC points macrophage numbers in injured nerves are normal. Bone marrow- CC derived macrophages from mutant mice display increased migration in CC response to CCL3, but not in the absence of CCL3 (PubMed:22729949). CC Mutant mice show dramatically increased survival in response to a dose CC of lipopolysaccharide (LPS) that causes rapid death of 40% of wild-type CC mice (PubMed:22160695). {ECO:0000269|PubMed:22160695, CC ECO:0000269|PubMed:22729949}. CC -!- SIMILARITY: Belongs to the CDIP1/LITAF family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAG44246.1; Type=Erroneous initiation; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF171100; AAF27312.1; -; mRNA. DR EMBL; AF230522; AAO49168.1; -; mRNA. DR EMBL; AK018578; BAB31289.1; -; mRNA. DR EMBL; AK076162; BAC36228.1; -; mRNA. DR EMBL; AK151053; BAE30070.1; -; mRNA. DR EMBL; AK159533; BAE35161.1; -; mRNA. DR EMBL; BC018559; AAH18559.1; -; mRNA. DR EMBL; AF220207; AAG44246.1; ALT_INIT; mRNA. DR CCDS; CCDS27958.1; -. DR RefSeq; NP_064364.1; NM_019980.2. DR RefSeq; XP_006522490.1; XM_006522427.1. DR AlphaFoldDB; Q9JLJ0; -. DR BioGRID; 208144; 2. DR IntAct; Q9JLJ0; 2. DR STRING; 10090.ENSMUSP00000023143; -. DR iPTMnet; Q9JLJ0; -. DR PhosphoSitePlus; Q9JLJ0; -. DR SwissPalm; Q9JLJ0; -. DR PaxDb; 10090-ENSMUSP00000023143; -. DR ProteomicsDB; 292265; -. DR Antibodypedia; 1839; 318 antibodies from 36 providers. DR DNASU; 56722; -. DR Ensembl; ENSMUST00000023143.14; ENSMUSP00000023143.8; ENSMUSG00000022500.16. DR Ensembl; ENSMUST00000117360.8; ENSMUSP00000112667.2; ENSMUSG00000022500.16. DR GeneID; 56722; -. DR KEGG; mmu:56722; -. DR UCSC; uc007yen.2; mouse. DR AGR; MGI:1929512; -. DR CTD; 9516; -. DR MGI; MGI:1929512; Litaf. DR VEuPathDB; HostDB:ENSMUSG00000022500; -. DR eggNOG; ENOG502S2GM; Eukaryota. DR GeneTree; ENSGT00940000155366; -. DR HOGENOM; CLU_095549_3_0_1; -. DR InParanoid; Q9JLJ0; -. DR OMA; VTFYDRP; -. DR OrthoDB; 1383925at2759; -. DR PhylomeDB; Q9JLJ0; -. DR TreeFam; TF313294; -. DR BioGRID-ORCS; 56722; 1 hit in 78 CRISPR screens. DR ChiTaRS; Litaf; mouse. DR PRO; PR:Q9JLJ0; -. DR Proteomes; UP000000589; Chromosome 16. DR RNAct; Q9JLJ0; Protein. DR Bgee; ENSMUSG00000022500; Expressed in granulocyte and 279 other cell types or tissues. DR ExpressionAtlas; Q9JLJ0; baseline and differential. DR GO; GO:0098559; C:cytoplasmic side of early endosome membrane; ISS:UniProtKB. DR GO; GO:0098560; C:cytoplasmic side of late endosome membrane; ISS:UniProtKB. DR GO; GO:0098574; C:cytoplasmic side of lysosomal membrane; ISS:UniProtKB. DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; ISS:UniProtKB. DR GO; GO:0005794; C:Golgi apparatus; ISS:UniProtKB. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI. DR GO; GO:0005765; C:lysosomal membrane; ISO:MGI. DR GO; GO:0005654; C:nucleoplasm; ISO:MGI. DR GO; GO:0005634; C:nucleus; IBA:GO_Central. DR GO; GO:0005886; C:plasma membrane; ISO:MGI. DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; ISO:MGI. DR GO; GO:0042802; F:identical protein binding; ISO:MGI. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; ISO:MGI. DR GO; GO:0050699; F:WW domain binding; ISS:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB. DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IMP:MGI. DR GO; GO:1901223; P:negative regulation of non-canonical NF-kappaB signal transduction; IMP:MGI. DR GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; ISS:UniProtKB. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISO:MGI. DR GO; GO:0001817; P:regulation of cytokine production; IBA:GO_Central. DR GO; GO:0010935; P:regulation of macrophage cytokine production; IMP:MGI. DR GO; GO:0032496; P:response to lipopolysaccharide; IMP:MGI. DR InterPro; IPR006629; LITAF. DR InterPro; IPR037519; LITAF_fam. DR PANTHER; PTHR23292; LIPOPOLYSACCHARIDE-INDUCED TUMOR NECROSIS FACTOR-ALPHA FACTOR; 1. DR PANTHER; PTHR23292:SF2; LIPOPOLYSACCHARIDE-INDUCED TUMOR NECROSIS FACTOR-ALPHA FACTOR; 1. DR Pfam; PF10601; zf-LITAF-like; 1. DR SMART; SM00714; LITAF; 1. DR PROSITE; PS51837; LITAF; 1. DR Genevisible; Q9JLJ0; MM. PE 1: Evidence at protein level; KW Cell membrane; Cytoplasm; DNA-binding; Endosome; Golgi apparatus; Lysosome; KW Membrane; Metal-binding; Nucleus; Reference proteome; Transcription; KW Transcription regulation; Zinc. FT CHAIN 1..161 FT /note="Lipopolysaccharide-induced tumor necrosis factor- FT alpha factor homolog" FT /id="PRO_0000084441" FT DOMAIN 76..160 FT /note="LITAF" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01181" FT REGION 111..134 FT /note="Membrane-binding amphipathic helix" FT /evidence="ECO:0000305" FT MOTIF 20..23 FT /note="PPxY motif" FT BINDING 96 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:Q99732" FT BINDING 99 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:Q99732" FT BINDING 148 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:Q99732" FT BINDING 151 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:Q99732" FT MUTAGEN 23 FT /note="Y->A: Abolishes interaction with NEDD4." FT /evidence="ECO:0000269|PubMed:11042109" FT MUTAGEN 61 FT /note="Y->A: No effect on interaction with NEDD4." FT /evidence="ECO:0000269|PubMed:11042109" SQ SEQUENCE 161 AA; 16946 MW; 7397F79C5AD0CD79 CRC64; MSAPGPYQAA AGPSVVPTAP PTYEETVGVN SYYPTPPAPM PGPATGLITG PDGKGMNPPS YYTQPVPVPN ANAIAVQTVY VQQPVSFYDR PVQMCCPSCS KMIVTQLSYN AGALTWLSCG SLCLLGCVAG CCFIPFCVDA LQDVDHYCPN CKALLGTYKR L //