RN186_HUMAN
ID RN186_HUMAN Reviewed; 227 AA.
AC Q9NXI6; Q53GE0;
DT 28-NOV-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2000, sequence version 1.
DT 03-AUG-2022, entry version 148.
DE RecName: Full=E3 ubiquitin-protein ligase RNF186 {ECO:0000305};
DE EC=2.3.2.27 {ECO:0000269|PubMed:23896122, ECO:0000269|PubMed:31586034, ECO:0000269|PubMed:33280498, ECO:0000269|PubMed:34623328};
DE AltName: Full=RING finger protein 186 {ECO:0000312|HGNC:HGNC:25978};
GN Name=RNF186 {ECO:0000312|HGNC:HGNC:25978};
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 [LARGE SCALE MRNA].
RC TISSUE=Colon mucosa;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Small intestine;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney, and Pancreas;
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 [6]
RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, INTERACTION WITH BNIP1, SUBCELLULAR
RP LOCATION, AUTOUBIQUITINATION, DOMAIN, AND MUTAGENESIS OF 58-CYS--CYS-66.
RX PubMed=23896122; DOI=10.1016/j.cellsig.2013.07.016;
RA Wang P., Wu Y., Li Y., Zheng J., Tang J.;
RT "A novel RING finger E3 ligase RNF186 regulate ER stress-mediated apoptosis
RT through interaction with BNip1.";
RL Cell. Signal. 25:2320-2333(2013).
RN [7]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF HIS-60.
RX PubMed=31586034; DOI=10.1074/jbc.ac119.010671;
RA Lear T.B., Lockwood K.C., Ouyang Y., Evankovich J.W., Larsen M.B., Lin B.,
RA Liu Y., Chen B.B.;
RT "The RING-type E3 ligase RNF186 ubiquitinates Sestrin-2 and thereby
RT controls nutrient sensing.";
RL J. Biol. Chem. 294:16527-16534(2019).
RN [8]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF ALA-64.
RX PubMed=33280498; DOI=10.1080/15548627.2020.1851496;
RA Zhang H., Cui Z., Cheng D., Du Y., Guo X., Gao R., Chen J., Sun W., He R.,
RA Ma X., Peng Q., Martin B.N., Yan W., Rong Y., Wang C.;
RT "RNF186 regulates EFNB1 (ephrin B1)-EPHB2-induced autophagy in the colonic
RT epithelial cells for the maintenance of intestinal homeostasis.";
RL Autophagy 17:3030-3047(2021).
RN [9]
RP FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=34623328; DOI=10.1172/jci145472;
RA Ranjan K., Hedl M., Sinha S., Zhang X., Abraham C.;
RT "Ubiquitination of ATF6 by disease-associated RNF186 promotes the innate
RT receptor-induced unfolded protein response.";
RL J. Clin. Invest. 131:0-0(2021).
CC -!- FUNCTION: E3 ubiquitin protein ligase that is part of an apoptotic
CC signaling pathway activated by endoplasmic reticulum stress
CC (PubMed:23896122). Stimulates the expression of proteins specific of
CC the unfolded protein response (UPR), ubiquitinates BNIP1 and regulates
CC its localization to the mitochondrion and induces calcium release from
CC the endoplasmic reticulum that ultimately leads to cell apoptosis
CC (PubMed:23896122). Plays a role in the maintenance of intestinal
CC homeostasis and clearance of enteric pathogens. Upon NOD2 stimulation,
CC ubiquitinates the ER stress sensor activating transcription factor
CC 6/ATF6 and promotes the unfolded protein response UPR
CC (PubMed:34623328). Participates in basal level of autophagy maintenance
CC by regulating the ubiquitination of EPHB2 and EPHB3. Upon stimulation
CC by ligand EFNB1, ubiquitinates EPHB2 and further recruits MAP1LC3B for
CC autophagy induction (PubMed:33280498). Controls nutrient sensing by
CC ubiquitinating Sestrin-2/SESN2, which is an intracellular sensor of
CC cytosolic leucine and inhibitor of mTORC1 activity (PubMed:31586034).
CC {ECO:0000269|PubMed:23896122, ECO:0000269|PubMed:31586034,
CC ECO:0000269|PubMed:33280498, ECO:0000269|PubMed:34623328}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.27; Evidence={ECO:0000269|PubMed:23896122,
CC ECO:0000269|PubMed:31586034, ECO:0000269|PubMed:33280498,
CC ECO:0000269|PubMed:34623328};
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000269|PubMed:23896122}.
CC -!- SUBUNIT: Interacts with BNIP1. {ECO:0000269|PubMed:23896122}.
CC -!- INTERACTION:
CC Q9NXI6; Q96AL5: PBX3; NbExp=3; IntAct=EBI-2129361, EBI-741171;
CC Q9NXI6; P57086: SCAND1; NbExp=3; IntAct=EBI-2129361, EBI-745846;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:23896122, ECO:0000269|PubMed:34623328}; Multi-pass
CC membrane protein {ECO:0000255}.
CC -!- DOMAIN: The RING-type domain is required for ubiquitination.
CC {ECO:0000269|PubMed:23896122}.
CC -!- PTM: Polyubiquitinated. 'Lys-29'-linked autoubiquitination leads to
CC proteasomal degradation. {ECO:0000269|PubMed:23896122}.
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DR EMBL; AK000232; BAA91024.1; -; mRNA.
DR EMBL; CR457228; CAG33509.1; -; mRNA.
DR EMBL; AK222991; BAD96711.1; -; mRNA.
DR EMBL; AL391883; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC030960; AAH30960.1; -; mRNA.
DR EMBL; BC051880; AAH51880.1; -; mRNA.
DR CCDS; CCDS199.1; -.
DR RefSeq; NP_061935.1; NM_019062.1.
DR AlphaFoldDB; Q9NXI6; -.
DR SMR; Q9NXI6; -.
DR BioGRID; 120033; 13.
DR IntAct; Q9NXI6; 4.
DR STRING; 9606.ENSP00000364263; -.
DR iPTMnet; Q9NXI6; -.
DR PhosphoSitePlus; Q9NXI6; -.
DR BioMuta; RNF186; -.
DR DMDM; 74761796; -.
DR PaxDb; Q9NXI6; -.
DR PeptideAtlas; Q9NXI6; -.
DR PRIDE; Q9NXI6; -.
DR Antibodypedia; 29735; 107 antibodies from 22 providers.
DR DNASU; 54546; -.
DR Ensembl; ENST00000375121.4; ENSP00000364263.2; ENSG00000178828.7.
DR GeneID; 54546; -.
DR KEGG; hsa:54546; -.
DR MANE-Select; ENST00000375121.4; ENSP00000364263.2; NM_019062.2; NP_061935.1.
DR UCSC; uc001bcr.3; human.
DR CTD; 54546; -.
DR DisGeNET; 54546; -.
DR GeneCards; RNF186; -.
DR HGNC; HGNC:25978; RNF186.
DR HPA; ENSG00000178828; Tissue enhanced (epididymis, intestine, pancreas).
DR neXtProt; NX_Q9NXI6; -.
DR OpenTargets; ENSG00000178828; -.
DR PharmGKB; PA142671057; -.
DR VEuPathDB; HostDB:ENSG00000178828; -.
DR eggNOG; KOG2177; Eukaryota.
DR GeneTree; ENSGT00510000049175; -.
DR HOGENOM; CLU_085235_0_0_1; -.
DR InParanoid; Q9NXI6; -.
DR OMA; EPYSCAR; -.
DR OrthoDB; 1446732at2759; -.
DR PhylomeDB; Q9NXI6; -.
DR TreeFam; TF331690; -.
DR BRENDA; 2.3.2.27; 2681.
DR PathwayCommons; Q9NXI6; -.
DR SignaLink; Q9NXI6; -.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 54546; 8 hits in 1109 CRISPR screens.
DR GenomeRNAi; 54546; -.
DR Pharos; Q9NXI6; Tbio.
DR PRO; PR:Q9NXI6; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; Q9NXI6; protein.
DR Bgee; ENSG00000178828; Expressed in jejunal mucosa and 66 other tissues.
DR Genevisible; Q9NXI6; HS.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IEA:InterPro.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:UniProtKB.
DR GO; GO:0070059; P:intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; IMP:UniProtKB.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IDA:UniProtKB.
DR GO; GO:0051865; P:protein autoubiquitination; IDA:UniProtKB.
DR GO; GO:0035519; P:protein K29-linked ubiquitination; IDA:UniProtKB.
DR GO; GO:0070534; P:protein K63-linked ubiquitination; IDA:UniProtKB.
DR GO; GO:0070585; P:protein localization to mitochondrion; IMP:UniProtKB.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR038878; RNF186.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR InterPro; IPR017907; Znf_RING_CS.
DR PANTHER; PTHR22791:SF21; PTHR22791:SF21; 1.
DR SMART; SM00184; RING; 1.
DR PROSITE; PS00518; ZF_RING_1; 1.
DR PROSITE; PS50089; ZF_RING_2; 1.
PE 1: Evidence at protein level;
KW Endoplasmic reticulum; Membrane; Metal-binding; Reference proteome;
KW Transferase; Transmembrane; Transmembrane helix; Ubl conjugation;
KW Ubl conjugation pathway; Zinc; Zinc-finger.
FT CHAIN 1..227
FT /note="E3 ubiquitin-protein ligase RNF186"
FT /id="PRO_0000261624"
FT TRANSMEM 158..178
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 180..200
FT /note="Helical"
FT /evidence="ECO:0000255"
FT ZN_FING 40..86
FT /note="RING-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT VARIANT 23
FT /note="A -> T (in dbSNP:rs1541185)"
FT /id="VAR_029460"
FT VARIANT 208
FT /note="P -> T (in dbSNP:rs35541730)"
FT /id="VAR_052111"
FT MUTAGEN 58..66
FT /note="CQHAFCAIC->AQWAFAAIA: Loss of autoubiquitination;
FT loss of BNIP1 polyubiquitination; no effect on interaction
FT with BNIP1; decreased effect on calcium release from the
FT endoplasmic reticulum."
FT /evidence="ECO:0000269|PubMed:23896122"
FT MUTAGEN 60
FT /note="H->W: Loss of ability to decrease SESN2 protein."
FT /evidence="ECO:0000269|PubMed:31586034"
FT MUTAGEN 64
FT /note="A->T: Exhibits a reduced ability to ubiquitinate
FT EPHB2 but retained ability to ubiquitinate EPHB3."
FT /evidence="ECO:0000269|PubMed:33280498"
FT CONFLICT 209
FT /note="S -> P (in Ref. 3; BAD96711)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 227 AA; 24145 MW; B856398C3C73DE3A CRC64;
MACTKTLQQS QPISAGATTT TTAVAPAGGH SGSTECDLEC LVCREPYSCP RLPKLLACQH
AFCAICLKLL LCVQDNTWSI TCPLCRKVTA VPGGLICSLR DHEAVVGQLA QPCTEVSLCP
QGLVDPADLA AGHPSLVGED GQDEVSANHV AARRLAAHLL LLALLIILIG PFIYPGVLRW
VLTFIIALAL LMSTLFCCLP STRGSCWPSS RTLFCREQKH SHISSIA
