Q8WU17 (RN139_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
E3 ubiquitin-protein ligase RNF139
EC=6.3.2.-

Alternative name(s):
RING finger protein 139
Translocation in renal carcinoma on chromosome 8 protein

Gene names

Name:	RNF139
Synonyms:	TRC8

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	664 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	E3-ubiquitin ligase; acts as a negative regulator of the cell proliferation through mechanisms involving G2/M arrest and cell death. Required for MHC class I ubiquitination in cells expressing the cytomegalovirus protein US2 before dislocation from the endoplasmic reticulum (ER). Affects SREBP processing by hindering the SREBP/SCAP complex translocation from the ER to the Golgi, thereby reducing SREBF2 target gene expression. Required for INSIG1 ubiquitination. May be required for EIF3 complex ubiquitination. May function as a signaling receptor. Ref.5 Ref.6 Ref.8 Ref.11 Ref.12 Ref.14
Pathway	Protein modification; protein ubiquitination.
Subunit structure	Interacts with VHL. Interacts with MHC class I and HM13. Component of SCAP/SREBP complex composed of SREBF2, SCAP and RNF139; the complex hampers the interaction between SCAP and SEC24B, thereby reducing SREBF2 proteolytic processing. Interacts with SREBF2 (via C-terminus domain). Interacts with SCAP; the interaction inhibits the interaction of SCAP with SEC24B and hampering the ER to Golgi transport of the SCAP/SREBP complex. Interacts with SEC24B. Interacts with INSIG1 and INSIG2. Interacts with EIF3F and EIF3H; the interaction leads to protein translation inhibitions in a ubiquitination-dependent manner. Ref.6 Ref.11 Ref.12 Ref.14
Subcellular location	Endoplasmic reticulum membrane; Multi-pass membrane protein Ref.6.
Tissue specificity	Highly expressed in testis, placenta and adrenal gland. Moderate expression in heart, brain, liver, skeletal muscle and pancreas, and low expression in lung and kidney. Ref.1
Induction	Down-regulated by sterols (at protein level). Ref.14
Domain	The RING-type zinc finger domain mediates ubiquitin ligase activity.
Post-translational modification	Autoubiquitinated. Ubiquitination is induced by sterol and leads to ist degradation via the ubiquitin-proteasome pathway.
Involvement in disease	Renal cell carcinoma (RCC) [MIM:144700]: Renal cell carcinoma is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. It is subclassified into clear cell renal carcinoma (non-papillary carcinoma), papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma with medullary carcinoma of the kidney, and unclassified renal cell carcinoma. Clear cell renal cell carcinoma is the most common subtype. Note: The disease may be caused by mutations affecting the gene represented in this entry. A chromosomal aberration involving RNF139 has been found in a lymphoblastoid cell line established from a family with renal cell carcinoma and thyroid carcinoma. Translocation (3;8)(q14.2;q24.1) with FHIT. RNF139 is found to be fused to FHIT and disrupted within the sterol-sensing domain. In contrast, the FHIT coding region is maintained and expressed. Sporadic cases of renal carcinoma, where an acquired mutation in RNF139 results in the duplication of 12 nucleotides in the 5'-UTR, has also been identified.
Sequence similarities	Contains 1 RING-type zinc finger.

Ontologies

Keywords
Biological process	Ubl conjugation pathway
Cellular component	Endoplasmic reticulum Membrane
Coding sequence diversity	Chromosomal rearrangement
Domain	Transmembrane Transmembrane helix Zinc-finger
Ligand	Metal-binding Zinc
Molecular function	Ligase Receptor
PTM	Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	negative regulation of cell proliferation Inferred from direct assay Ref.8. Source: UniProtKB negative regulation of translation Inferred from direct assay Ref.14. Source: UniProtKB regulation of ER to Golgi vesicle-mediated transport Inferred from direct assay Ref.11. Source: UniProtKB regulation of protein processing Inferred from direct assay Ref.11. Source: UniProtKB regulation of protein ubiquitination Inferred from direct assay Ref.5. Source: UniProtKB
Cellular_component	endoplasmic reticulum Inferred from direct assay Ref.6. Source: UniProtKB endoplasmic reticulum membrane Inferred from electronic annotation. Source: UniProtKB-SubCell integral to membrane Traceable author statement Ref.6. Source: UniProtKB
Molecular_function	receptor activity Traceable author statement Ref.1. Source: UniProtKB ubiquitin-protein ligase activity Inferred from direct assay Ref.8. Source: UniProtKB zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
VHL	P40337	2	EBI-1551681,EBI-301246

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 664	664	E3 ubiquitin-protein ligase RNF139		PRO_0000056098
Regions
	Transmembrane	51 – 71	21	Helical; Potential
	Transmembrane	85 – 105	21	Helical; Potential
	Transmembrane	125 – 145	21	Helical; Potential
	Transmembrane	154 – 174	21	Helical; Potential
	Transmembrane	178 – 198	21	Helical; Potential
	Transmembrane	293 – 313	21	Helical; Potential
	Transmembrane	323 – 343	21	Helical; Potential
	Transmembrane	356 – 376	21	Helical; Potential
	Transmembrane	390 – 410	21	Helical; Potential
	Transmembrane	420 – 440	21	Helical; Potential
	Transmembrane	469 – 489	21	Helical; Potential
	Transmembrane	495 – 512	18	Helical; Potential
	Zinc finger	547 – 586	40	RING-type; atypical
Amino acid modifications
	Modified residue	663	1	Phosphothreonine Ref.7 Ref.9 Ref.10 Ref.13 Ref.15 Ref.16
Experimental info
	Mutagenesis	547 – 586	40	Missing: Increases proliferation. Rescues MHC class I to the cell surface. Fails to down-regulate SREBF1 and SREBF2. Ref.11 Ref.12 Ref.14
	Mutagenesis	547 – 550	4	CAIC → SAIS: Abolishes ubiquitination activity. Increases proliferation. Does not phosphorylates CHEK2 on T-68. Does not phosphorylates ATM on S-1981. Rescues MHC class I to the cell surface. Suppresses SREBF2 processing in the presence or absence of sterols. Fails to down-regulate SREBF1 and SREBF2. Decreases INSIG1 ubiquitination. Ref.11 Ref.12 Ref.14
	Mutagenesis	557 – 559	3	SAR → AAA: Retaines about 30% of ubiquitination activity.
	Mutagenesis	572 – 574	3	LRK → AAA: Abolishes ubiquitination activity. Increases proliferation. Ref.8
	Mutagenesis	582 – 585	4	CPMC → APMA: Abolishes ubiquitination activity. Increases proliferation. Ref.8
	Sequence conflict	18	1	V → I in AAC39930. Ref.1
	Sequence conflict	18	1	V → I in AAC39931. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Q8WU17 [UniParc]. Last modified March 1, 2002. Version 1. Checksum: 9885F5915F019EF5	FASTA	664	75,994
	10 20 30 40 50 60 MAAVGPPQQQ VRMAHQQVWA ALEVALRVPC LYIIDAIFNS YPDSSQSRFC IVLQIFLRLF 70 80 90 100 110 120 GVFASSIVLI LSQRSLFKFY TYSSAFLLAA TSVLVNYYAS LHIDFYGAYN TSAFGIELLP 130 140 150 160 170 180 RKGPSLWMAL IVLQLTFGIG YVTLLQIHSI YSQLIILDLL VPVIGLITEL PLHIRETLLF 190 200 210 220 230 240 TSSLILTLNT VFVLAVKLKW FYYSTRYVYL LVRHMYRIYG LQLLMEDTWK RIRFPDILRV 250 260 270 280 290 300 FWLTRVTAQA TVLMYILRMA NETDSFFISW DDFWDLICNL IISGCDSTLT VLGMSAVISS 310 320 330 340 350 360 VAHYLGLGIL AFIGSTEEDD RRLGFVAPVL FFILALQTGL SGLRPEERLI RLSRNMCLLL 370 380 390 400 410 420 TAVLHFIHGM TDPVLMSLSA SHVSSFRRHF PVLFVSACLF ILPVLLSYVL WHHYALNTWL 430 440 450 460 470 480 FAVTAFCVEL CLKVIVSLTV YTLFMIDGYY NVLWEKLDDY VYYVRSTGSI IEFIFGVVMF 490 500 510 520 530 540 GNGAYTMMFE SGSKIRAFMM CLHAYFNIYL QAKNGWKTFM NRRTAVKKIN SLPEIKGSRL 550 560 570 580 590 600 QEINDVCAIC YHEFTTSARI TPCNHYFHAL CLRKWLYIQD TCPMCHQKVY IEDDIKDNSN 610 620 630 640 650 660 VSNNNGFIPP NETPEEAVRE AAAESDRELN EDDSTDCDDD VQRERNGVIQ HTGAAAEEFN DDTD

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched-related gene, TRC8." Gemmill R.M., West J.D., Boldog F., Tanaka N., Robinson L.J., Smith D.I., Li F., Drabkin H.A. Proc. Natl. Acad. Sci. U.S.A. 95:9572-9577(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-60, TISSUE SPECIFICITY, CHROMOSOMAL TRANSLOCATION WITH FHIT.
[2]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[3]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Lung and Pancreas.
[5]	"RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination." Lorick K.L., Jensen J.P., Fang S., Ong A.M., Hatakeyama S., Weissman A.M. Proc. Natl. Acad. Sci. U.S.A. 96:11364-11369(1999) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[6]	"The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway." Gemmill R.M., Bemis L.T., Lee J.P., Sozen M.A., Baron A., Zeng C., Erickson P.F., Hooper J.E., Drabkin H.A. Oncogene 21:3507-3516(2002) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH VHL, SUBCELLULAR LOCATION.
[7]	"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks." Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M. Cell 127:635-648(2006) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-663, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[8]	"RING-dependent tumor suppression and G2/M arrest induced by the TRC8 hereditary kidney cancer gene." Brauweiler A., Lorick K.L., Lee J.P., Tsai Y.C., Chan D., Weissman A.M., Drabkin H.A., Gemmill R.M. Oncogene 26:2263-2271(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF 547-CYS--CYS-550; 547-CYS--HIS-586; 557-SER--ARG-559; 572-LEU--LYS-574 AND 582-CYS--CYS-585.
[9]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-663, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[10]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-663, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[11]	"The sterol-sensing endoplasmic reticulum (ER) membrane protein TRC8 hampers ER to Golgi transport of sterol regulatory element-binding protein-2 (SREBP-2)/SREBP cleavage-activated protein and reduces SREBP-2 cleavage." Irisawa M., Inoue J., Ozawa N., Mori K., Sato R. J. Biol. Chem. 284:28995-29004(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH SREBF2; SCAP AND SEC24B, UBIQUITINATION, MUTAGENESIS OF 547-CYS--CYS-550 AND 547-CYS--HIS-586.
[12]	"The TRC8 E3 ligase ubiquitinates MHC class I molecules before dislocation from the ER." Stagg H.R., Thomas M., van den Boomen D., Wiertz E.J., Drabkin H.A., Gemmill R.M., Lehner P.J. J. Cell Biol. 186:685-692(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH MHC CLASS I AND HM13, MUTAGENESIS OF 547-CYS--CYS-550 AND 547-CYS--HIS-586.
[13]	"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions." Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K. Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-663, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[14]	"The TRC8 ubiquitin ligase is sterol regulated and interacts with lipid and protein biosynthetic pathways." Lee J.P., Brauweiler A., Rudolph M., Hooper J.E., Drabkin H.A., Gemmill R.M. Mol. Cancer Res. 8:93-106(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH INSIG1; INSIG2; EIF3F AND EIF3H, INDUCTION, MUTAGENESIS OF 547-CYS--CYS-550 AND 547-CYS--HIS-586.
[15]	"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis." Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M. Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-663, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[16]	"System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation." Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B. Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-663, MASS SPECTROMETRY.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF064800 Genomic DNA. Translation: AAC39931.1. AF064801 mRNA. Translation: AAC39930.1. AK001602 mRNA. Translation: BAG50947.1. CH471060 Genomic DNA. Translation: EAW92064.1. BC021571 mRNA. Translation: AAH21571.1. BC064636 mRNA. Translation: AAH64636.1.
IPI	IPI00289584.
RefSeq	NP_009149.2. NM_007218.3.
UniGene	Hs.730771.
3D structure databases
ProteinModelPortal	Q8WU17.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q8WU17. 4 interactions.
STRING	9606.ENSP00000304051.
PTM databases
PhosphoSite	Q8WU17.
Polymorphism databases
DMDM	74760542.
Proteomic databases
PaxDb	Q8WU17.
PRIDE	Q8WU17.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000303545; ENSP00000304051; ENSG00000170881.
GeneID	11236.
KEGG	hsa:11236.
UCSC	uc003yrc.3. human.
Organism-specific databases
CTD	11236.
GeneCards	GC08P125487.
HGNC	HGNC:17023. RNF139.
HPA	HPA001202.
MIM	144700. phenotype. 603046. gene.
neXtProt	NX_Q8WU17.
Orphanet	151. Familial renal cell carcinoma.
PharmGKB	PA134945850.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG246550.
HOGENOM	HOG000267029.
HOVERGEN	HBG053146.
InParanoid	Q8WU17.
KO	K15703.
OMA	RIRFPDI.
OrthoDB	EOG4H4638.
PhylomeDB	Q8WU17.
Enzyme and pathway databases
UniPathway	UPA00143.
Gene expression databases
ArrayExpress	Q8WU17.
Bgee	Q8WU17.
CleanEx	HS_RNF139.
Genevestigator	Q8WU17.
GermOnline	ENSG00000170881. Homo sapiens.
Family and domain databases
Gene3D	3.30.40.10. 1 hit.
InterPro	IPR025754. TRC8_N_dom. IPR001841. Znf_RING. IPR013083. Znf_RING/FYVE/PHD. [Graphical view]
Pfam	PF13705. TRC8_N. 1 hit. PF13639. zf-RING_2. 1 hit. [Graphical view]
SMART	SM00184. RING. 1 hit. [Graphical view]
PROSITE	PS00518. ZF_RING_1. False negative. PS50089. ZF_RING_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
GenomeRNAi	11236.
NextBio	42766.
SOURCE	Search...

Entry information

Entry name

RN139_HUMAN

Accession

Primary (citable) accession number: Q8WU17
Secondary accession number(s): B3KMD5, O75485, Q7LDL3

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 6, 2005
Last sequence update:	March 1, 2002
Last modified:	May 1, 2013
This is version 106 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.