ID   FAF2_HUMAN              Reviewed;         445 AA.
AC   Q96CS3; O94963; Q8IUF2; Q9BRP2; Q9BVM7;
DT   27-JUN-2006, integrated into UniProtKB/Swiss-Prot.
DT   01-MAR-2004, sequence version 2.
DT   10-JUN-2026, entry version 190.
DE   RecName: Full=FAS-associated factor 2;
DE   AltName: Full=UBX domain-containing protein 3B;
DE   AltName: Full=UBX domain-containing protein 8;
GN   Name=FAF2 {ECO:0000303|PubMed:34739333, ECO:0000312|HGNC:HGNC:24666};
GN   Synonyms=ETEA {ECO:0000303|PubMed:12372427}, KIAA0887
GN   {ECO:0000303|PubMed:10048485}, UBXD8, UBXN3B;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RC   TISSUE=T-cell;
RX   PubMed=12372427; DOI=10.1016/s0006-291x(02)02380-x;
RA   Imai Y., Nakada A., Hashida R., Sugita Y., Tanaka T., Tsujimoto G.,
RA   Matsumoto K., Akasawa A., Saito H., Oshida T.;
RT   "Cloning and characterization of the highly expressed ETEA gene from blood
RT   cells of atopic dermatitis patients.";
RL   Biochem. Biophys. Res. Commun. 297:1282-1290(2002).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Lung, and Muscle;
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   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 3-445.
RC   TISSUE=Brain;
RX   PubMed=10048485; DOI=10.1093/dnares/5.6.355;
RA   Nagase T., Ishikawa K., Suyama M., Kikuno R., Hirosawa M., Miyajima N.,
RA   Tanaka A., Kotani H., Nomura N., Ohara O.;
RT   "Prediction of the coding sequences of unidentified human genes. XII. The
RT   complete sequences of 100 new cDNA clones from brain which code for large
RT   proteins in vitro.";
RL   DNA Res. 5:355-364(1998).
RN   [4]
RP   IDENTIFICATION IN A COMPLEX WITH SEL1L, SUBCELLULAR LOCATION, AND FUNCTION.
RX   PubMed=18711132; DOI=10.1073/pnas.0805371105;
RA   Mueller B., Klemm E.J., Spooner E., Claessen J.H., Ploegh H.L.;
RT   "SEL1L nucleates a protein complex required for dislocation of misfolded
RT   glycoproteins.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:12325-12330(2008).
RN   [5]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP   METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP   [LARGE SCALE ANALYSIS].
RX   PubMed=19413330; DOI=10.1021/ac9004309;
RA   Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT   "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT   refined SCX-based approach.";
RL   Anal. Chem. 81:4493-4501(2009).
RN   [6]
RP   SUBCELLULAR LOCATION.
RX   PubMed=19773358; DOI=10.1242/jcs.054700;
RA   Zehmer J.K., Bartz R., Bisel B., Liu P., Seemann J., Anderson R.G.W.;
RT   "Targeting sequences of UBXD8 and AAM-B reveal that the ER has a direct
RT   role in the emergence and regression of lipid droplets.";
RL   J. Cell Sci. 122:3694-3702(2009).
RN   [7]
RP   INTERACTION WITH YOD1.
RX   PubMed=19818707; DOI=10.1016/j.molcel.2009.09.016;
RA   Ernst R., Mueller B., Ploegh H.L., Schlieker C.;
RT   "The otubain YOD1 is a deubiquitinating enzyme that associates with p97 to
RT   facilitate protein dislocation from the ER.";
RL   Mol. Cell 36:28-38(2009).
RN   [8]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-167, AND IDENTIFICATION BY MASS
RP   SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19608861; DOI=10.1126/science.1175371;
RA   Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA   Olsen J.V., Mann M.;
RT   "Lysine acetylation targets protein complexes and co-regulates major
RT   cellular functions.";
RL   Science 325:834-840(2009).
RN   [9]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [10]
RP   FUNCTION, INTERACTION WITH PNPLA2 AND UBAC2, AND SUBCELLULAR LOCATION.
RX   PubMed=23297223; DOI=10.1073/pnas.1213738110;
RA   Olzmann J.A., Richter C.M., Kopito R.R.;
RT   "Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediated lipid
RT   droplet turnover.";
RL   Proc. Natl. Acad. Sci. U.S.A. 110:1345-1350(2013).
RN   [11]
RP   INTERACTION WITH ZFAND2B.
RX   PubMed=24160817; DOI=10.1042/bj20130710;
RA   Glinka T., Alter J., Braunstein I., Tzach L., Wei Sheng C., Geifman S.,
RA   Edelmann M.J., Kessler B.M., Stanhill A.;
RT   "Signal-peptide-mediated translocation is regulated by a p97-AIRAPL
RT   complex.";
RL   Biochem. J. 457:253-261(2014).
RN   [12]
RP   FUNCTION, AND INTERACTION WITH UBQLN2.
RX   PubMed=24215460; DOI=10.1111/jnc.12606;
RA   Xia Y., Yan L.H., Huang B., Liu M., Liu X., Huang C.;
RT   "Pathogenic mutation of UBQLN2 impairs its interaction with UBXD8 and
RT   disrupts endoplasmic reticulum-associated protein degradation.";
RL   J. Neurochem. 129:99-106(2014).
RN   [13]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA   Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA   Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT   phosphoproteome.";
RL   J. Proteomics 96:253-262(2014).
RN   [14]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=25944712; DOI=10.1002/pmic.201400617;
RA   Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA   Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT   "N-terminome analysis of the human mitochondrial proteome.";
RL   Proteomics 15:2519-2524(2015).
RN   [15]
RP   FUNCTION.
RX   PubMed=26692333; DOI=10.1038/nm.4013;
RA   Osorio F.G., Soria-Valles C., Santiago-Fernandez O., Bernal T.,
RA   Mittelbrunn M., Colado E., Rodriguez F., Bonzon-Kulichenko E., Vazquez J.,
RA   Porta-de-la-Riva M., Ceron J., Fueyo A., Li J., Green A.R., Freije J.M.,
RA   Lopez-Otin C.;
RT   "Loss of the proteostasis factor AIRAPL causes myeloid transformation by
RT   deregulating IGF-1 signaling.";
RL   Nat. Med. 22:91-96(2016).
RN   [16]
RP   INTERACTION WITH LMBR1L.
RX   PubMed=31073040; DOI=10.1126/science.aau0812;
RA   Choi J.H., Zhong X., McAlpine W., Liao T.C., Zhang D., Fang B., Russell J.,
RA   Ludwig S., Nair-Gill E., Zhang Z., Wang K.W., Misawa T., Zhan X., Choi M.,
RA   Wang T., Li X., Tang M., Sun Q., Yu L., Murray A.R., Moresco E.M.Y.,
RA   Beutler B.;
RT   "LMBR1L regulates lymphopoiesis through Wnt/beta-catenin signaling.";
RL   Science 364:0-0(2019).
RN   [17]
RP   FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=34739333; DOI=10.1126/science.abf6548;
RA   Gwon Y., Maxwell B.A., Kolaitis R.M., Zhang P., Kim H.J., Taylor J.P.;
RT   "Ubiquitination of G3BP1 mediates stress granule disassembly in a context-
RT   specific manner.";
RL   Science 372:eabf6548-eabf6548(2021).
RN   [18]
RP   STRUCTURE BY NMR OF 3-56.
RG   RIKEN structural genomics initiative (RSGI);
RT   "Solution structure of the novel identified UBA-like domain in the N-
RT   terminal of human ETEA protein.";
RL   Submitted (JUN-2006) to the PDB data bank.
CC   -!- FUNCTION: Plays an important role in endoplasmic reticulum-associated
CC       degradation (ERAD) that mediates ubiquitin-dependent degradation of
CC       misfolded endoplasmic reticulum proteins (PubMed:18711132,
CC       PubMed:24215460). By controlling the steady-state expression of the
CC       IGF1R receptor, indirectly regulates the insulin-like growth factor
CC       receptor signaling pathway (PubMed:26692333). Recruits ATPase VCP to
CC       lipid droplets and also binds to phospholipase PNPLA2/ATGL, inhibiting
CC       PNPLA2 activity by promoting its dissociation from its ABHD5/CGI-58
CC       activator (PubMed:23297223). This inhibits PNPLA2-mediated
CC       triacylglycerol hydrolysis and leads to inhibition of lipid droplet
CC       degradation (PubMed:23297223). Involved in stress granule disassembly:
CC       associates with ubiquitinated G3BP1 in response to heat shock, thereby
CC       promoting interaction between ubiquitinated G3BP1 and VCP, followed by
CC       G3BP1 extraction from stress granules and stress granule disassembly
CC       (PubMed:34739333). {ECO:0000269|PubMed:18711132,
CC       ECO:0000269|PubMed:23297223, ECO:0000269|PubMed:24215460,
CC       ECO:0000269|PubMed:26692333, ECO:0000269|PubMed:34739333}.
CC   -!- SUBUNIT: Identified in a complex that contains SEL1L, OS9, FAF2/UBXD8,
CC       UBE2J1/UBC6E and AUP1 (PubMed:18711132). Interacts with YOD1
CC       (PubMed:19818707). Interacts (via N-terminus) with UBQLN2 (via C-
CC       terminus) (PubMed:24215460). Interacts with PNPLA2; inhibits PNPLA2
CC       activity (PubMed:23297223). Interacts with UBAC2; the interaction
CC       restricts trafficking of FAF2 from the endoplasmic reticulum to lipid
CC       droplets (PubMed:23297223). Interacts with ZFAND2B; probably through
CC       VCP (PubMed:24160817). Interacts with LMBR1L (PubMed:31073040).
CC       {ECO:0000269|PubMed:18711132, ECO:0000269|PubMed:19818707,
CC       ECO:0000269|PubMed:23297223, ECO:0000269|PubMed:24160817,
CC       ECO:0000269|PubMed:24215460, ECO:0000305|PubMed:31073040}.
CC   -!- INTERACTION:
CC       Q96CS3; Q8NBM4: UBAC2; NbExp=8; IntAct=EBI-1055805, EBI-724045;
CC       Q96CS3; P50552: VASP; NbExp=2; IntAct=EBI-1055805, EBI-748201;
CC       Q96CS3; P55072: VCP; NbExp=16; IntAct=EBI-1055805, EBI-355164;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:12372427}. Lipid
CC       droplet {ECO:0000269|PubMed:19773358, ECO:0000269|PubMed:23297223}.
CC       Endoplasmic reticulum {ECO:0000269|PubMed:18711132,
CC       ECO:0000269|PubMed:23297223, ECO:0000269|PubMed:34739333}.
CC   -!- TISSUE SPECIFICITY: Broadly expressed, with highest levels in brain.
CC       {ECO:0000269|PubMed:12372427}.
CC   -!- MISCELLANEOUS: Up-regulated in T-cells and eosinophils from patients
CC       with atopic dermatitis.
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DR   EMBL; AB088120; BAC22491.1; -; mRNA.
DR   EMBL; BC001069; AAH01069.2; -; mRNA.
DR   EMBL; BC006145; AAH06145.2; -; mRNA.
DR   EMBL; BC014001; AAH14001.2; -; mRNA.
DR   EMBL; AB020694; BAA74910.1; -; mRNA.
DR   CCDS; CCDS34296.1; -.
DR   RefSeq; NP_055428.1; NM_014613.3.
DR   PDB; 2DAM; NMR; -; A=3-56.
DR   PDBsum; 2DAM; -.
DR   AlphaFoldDB; Q96CS3; -.
DR   BMRB; Q96CS3; -.
DR   SMR; Q96CS3; -.
DR   BioGRID; 116806; 507.
DR   ComplexPortal; CPX-8104; VCP-NPL4-UFD1-FAF2 AAA ATPase complex.
DR   CORUM; Q96CS3; -.
DR   DIP; DIP-46261N; -.
DR   FunCoup; Q96CS3; 3619.
DR   IntAct; Q96CS3; 238.
DR   MINT; Q96CS3; -.
DR   NDEx; IQUERY-CP-FAF2; 1 NDEx IQuery Curated Pathway.
DR   STRING; 9606.ENSP00000261942; -.
DR   GlyGen; Q96CS3; 3 sites, 1 N-linked glycan (1 site), 1 O-linked glycan (2 sites).
DR   iPTMnet; Q96CS3; -.
DR   MetOSite; Q96CS3; -.
DR   PhosphoSitePlus; Q96CS3; -.
DR   SwissPalm; Q96CS3; -.
DR   BioMuta; FAF2; -.
DR   DMDM; 74731375; -.
DR   jPOST; Q96CS3; -.
DR   MassIVE; Q96CS3; -.
DR   PaxDb; 9606-ENSP00000261942; -.
DR   PeptideAtlas; Q96CS3; -.
DR   ProteomicsDB; 76214; -.
DR   Pumba; Q96CS3; -.
DR   Antibodypedia; 29092; 206 antibodies from 34 providers.
DR   DNASU; 23197; -.
DR   Ensembl; ENST00000261942.7; ENSP00000261942.6; ENSG00000113194.14.
DR   GeneID; 23197; -.
DR   KEGG; hsa:23197; -.
DR   MANE-Select; ENST00000261942.7; ENSP00000261942.6; NM_014613.3; NP_055428.1.
DR   UCSC; uc003mej.4; human.
DR   AGR; HGNC:24666; -.
DR   ClinPGx; PA162385570; -.
DR   CTD; 23197; -.
DR   DisGeNET; 23197; -.
DR   GeneCards; FAF2; -.
DR   HGNC; HGNC:24666; FAF2.
DR   HPA; ENSG00000113194; Low tissue specificity.
DR   MIM; 616935; gene.
DR   OpenTargets; ENSG00000113194; -.
DR   VEuPathDB; HostDB:ENSG00000113194; -.
DR   eggNOG; KOG1363; Eukaryota.
DR   GeneTree; ENSGT00940000157197; -.
DR   HOGENOM; CLU_047924_0_0_1; -.
DR   InParanoid; Q96CS3; -.
DR   OMA; ILIRHQW; -.
DR   OrthoDB; 1026733at2759; -.
DR   PAN-GO; Q96CS3; 3 GO annotations based on evolutionary models.
DR   PhylomeDB; Q96CS3; -.
DR   PathwayCommons; Q96CS3; -.
DR   Reactome; R-HSA-6798695; Neutrophil degranulation.
DR   Reactome; R-HSA-8980692; RHOA GTPase cycle.
DR   SignaLink; Q96CS3; -.
DR   SIGNOR; Q96CS3; -.
DR   Agora; ENSG00000113194; -.
DR   BioGRID-ORCS; 23197; 304 hits in 1160 CRISPR screens.
DR   ChiTaRS; FAF2; human.
DR   EvolutionaryTrace; Q96CS3; -.
DR   GenomeRNAi; 23197; -.
DR   Pharos; Q96CS3; Tbio.
DR   PRO; PR:Q96CS3; -.
DR   Proteomes; UP000005640; Chromosome 5.
DR   RNAct; Q96CS3; protein.
DR   Bgee; ENSG00000113194; Expressed in parotid gland and 203 other cell types or tissues.
DR   ExpressionAtlas; Q96CS3; baseline and differential.
DR   GO; GO:0035578; C:azurophil granule lumen; TAS:Reactome.
DR   GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR   GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR   GO; GO:0005811; C:lipid droplet; IDA:UniProtKB.
DR   GO; GO:0034098; C:VCP-NPL4-UFD1 AAA ATPase complex; IDA:BHF-UCL.
DR   GO; GO:0035473; F:lipase binding; IDA:MGI.
DR   GO; GO:0055102; F:lipase inhibitor activity; IDA:MGI.
DR   GO; GO:0030674; F:protein-macromolecule adaptor activity; IDA:UniProtKB.
DR   GO; GO:0043130; F:ubiquitin binding; IDA:BHF-UCL.
DR   GO; GO:0031625; F:ubiquitin protein ligase binding; IDA:BHF-UCL.
DR   GO; GO:0036503; P:ERAD pathway; IMP:UniProtKB.
DR   GO; GO:0034389; P:lipid droplet organization; IMP:MGI.
DR   GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IEA:Ensembl.
DR   GO; GO:0006986; P:response to unfolded protein; IEA:UniProtKB-KW.
DR   GO; GO:0030970; P:retrograde protein transport, ER to cytosol; IMP:ParkinsonsUK-UCL.
DR   GO; GO:0035617; P:stress granule disassembly; IDA:UniProtKB.
DR   CDD; cd02991; UAS_ETEA; 1.
DR   CDD; cd14414; UBA_FAF2; 1.
DR   CDD; cd16120; UBX_UBXN3B; 1.
DR   FunFam; 3.10.20.90:FF:000101; FAS-associated factor 2 isoform X2; 1.
DR   FunFam; 3.40.30.10:FF:000066; FAS-associated factor 2 isoform X2; 1.
DR   FunFam; 1.10.8.10:FF:000043; Fas-associated factor family member 2; 1.
DR   Gene3D; 1.10.8.10; DNA helicase RuvA subunit, C-terminal domain; 1.
DR   Gene3D; 3.40.30.10; Glutaredoxin; 1.
DR   Gene3D; 3.10.20.90; Phosphatidylinositol 3-kinase Catalytic Subunit, Chain A, domain 1; 1.
DR   InterPro; IPR049483; FAF1_2-like_UAS.
DR   InterPro; IPR036249; Thioredoxin-like_sf.
DR   InterPro; IPR006577; UAS.
DR   InterPro; IPR009060; UBA-like_sf.
DR   InterPro; IPR054109; UBA_8.
DR   InterPro; IPR029071; Ubiquitin-like_domsf.
DR   InterPro; IPR001012; UBX_dom.
DR   InterPro; IPR050730; UBX_domain-protein.
DR   PANTHER; PTHR23322:SF1; FAS-ASSOCIATED FACTOR 2; 1.
DR   PANTHER; PTHR23322; FAS-ASSOCIATED PROTEIN; 1.
DR   Pfam; PF21021; FAF1; 1.
DR   Pfam; PF22566; UBA_8; 1.
DR   Pfam; PF00789; UBX; 1.
DR   SMART; SM00594; UAS; 1.
DR   SUPFAM; SSF52833; Thioredoxin-like; 1.
DR   SUPFAM; SSF46934; UBA-like; 1.
DR   SUPFAM; SSF54236; Ubiquitin-like; 1.
DR   PROSITE; PS50033; UBX; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Coiled coil; Cytoplasm; Endoplasmic reticulum;
KW   Lipid droplet; Proteomics identification; Reference proteome;
KW   Unfolded protein response.
FT   INIT_MET        1
FT                   /note="Removed"
FT                   /evidence="ECO:0007744|PubMed:19413330"
FT   CHAIN           2..445
FT                   /note="FAS-associated factor 2"
FT                   /id="PRO_0000244064"
FT   DOMAIN          12..48
FT                   /note="UBA"
FT   DOMAIN          357..439
FT                   /note="UBX"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00215"
FT   REGION          299..361
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COILED          275..350
FT                   /evidence="ECO:0000255"
FT   COMPBIAS        303..348
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOD_RES         2
FT                   /note="N-acetylalanine"
FT                   /evidence="ECO:0007744|PubMed:19413330"
FT   MOD_RES         167
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0007744|PubMed:19608861"
FT   HELIX           11..24
FT                   /evidence="ECO:0007829|PDB:2DAM"
FT   HELIX           29..39
FT                   /evidence="ECO:0007829|PDB:2DAM"
FT   HELIX           43..52
FT                   /evidence="ECO:0007829|PDB:2DAM"
SQ   SEQUENCE   445 AA;  52623 MW;  D5510BCB0623096B CRC64;
     MAAPEERDLT QEQTEKLLQF QDLTGIESMD QCRHTLEQHN WNIEAAVQDR LNEQEGVPSV
     FNPPPSRPLQ VNTADHRIYS YVVSRPQPRG LLGWGYYLIM LPFRFTYYTI LDIFRFALRF
     IRPDPRSRVT DPVGDIVSFM HSFEEKYGRA HPVFYQGTYS QALNDAKREL RFLLVYLHGD
     DHQDSDEFCR NTLCAPEVIS LINTRMLFWA CSTNKPEGYR VSQALRENTY PFLAMIMLKD
     RRMTVVGRLE GLIQPDDLIN QLTFIMDANQ TYLVSERLER EERNQTQVLR QQQDEAYLAS
     LRADQEKERK KREERERKRR KEEEVQQQKL AEERRRQNLQ EEKERKLECL PPEPSPDDPE
     SVKIIFKLPN DSRVERRFHF SQSLTVIHDF LFSLKESPEK FQIEANFPRR VLPCIPSEEW
     PNPPTLQEAG LSHTEVLFVQ DLTDE
//