MEFV_MOUSE
ID MEFV_MOUSE Reviewed; 767 AA.
AC Q9JJ26; E9QN30;
DT 19-SEP-2003, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 2.
DT 03-AUG-2022, entry version 142.
DE RecName: Full=Pyrin {ECO:0000303|PubMed:23226472};
GN Name=Mefv {ECO:0000303|PubMed:10818206, ECO:0000312|MGI:MGI:1859396};
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 {ECO:0000312|EMBL:AAF03766.1};
RN [1] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC STRAIN=129/Sv;
RX PubMed=10818206; DOI=10.1007/s003350010082;
RA Chae J.J., Centola M., Aksentijevich I., Dutra A., Tran M., Wood G.,
RA Nagaraju K., Kingma D.W., Liu P.P., Kastner D.L.;
RT "Isolation, genomic organization, and expression analysis of the mouse and
RT rat homologs of MEFV, the gene for familial Mediterranean fever.";
RL Mamm. Genome 11:428-435(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [3]
RP DISRUPTION PHENOTYPE.
RX PubMed=23226472; DOI=10.1371/journal.pone.0051105;
RA Hesker P.R., Nguyen M., Kovarova M., Ting J.P., Koller B.H.;
RT "Genetic loss of murine pyrin, the Familial Mediterranean Fever protein,
RT increases interleukin-1beta levels.";
RL PLoS ONE 7:E51105-E51105(2012).
RN [4]
RP FUNCTION, AND IDENTIFICATION IN THE AIM2 PANOPTOSOME COMPLEX.
RX PubMed=34471287; DOI=10.1038/s41586-021-03875-8;
RA Lee S., Karki R., Wang Y., Nguyen L.N., Kalathur R.C., Kanneganti T.D.;
RT "AIM2 forms a complex with pyrin and ZBP1 to drive PANoptosis and host
RT defence.";
RL Nature 597:415-419(2021).
CC -!- FUNCTION: Involved in the regulation of innate immunity and the
CC inflammatory response in response to IFNG/IFN-gamma (PubMed:34471287).
CC Organizes autophagic machinery by serving as a platform for the
CC assembly of ULK1, Beclin 1/BECN1, ATG16L1, and ATG8 family members and
CC recognizes specific autophagy targets, thus coordinating target
CC recognition with assembly of the autophagic apparatus and initiation of
CC autophagy (By similarity). Acts as an autophagy receptor for the
CC degradation of several inflammasome components, including CASP1, NLRP1
CC and NLRP3, hence preventing excessive IL1B- and IL18-mediated
CC inflammation (By similarity). However, it can also have a positive
CC effect in the inflammatory pathway, acting as an innate immune sensor
CC that triggers PYCARD/ASC specks formation, caspase-1 activation, and
CC IL1B and IL18 production (By similarity). Together with AIM2, also acts
CC as a mediator of pyroptosis, necroptosis and apoptosis (PANoptosis), an
CC integral part of host defense against pathogens, in response to
CC bacterial infection (PubMed:34471287). It is required for PSTPIP1-
CC induced PYCARD/ASC oligomerization and inflammasome formation (By
CC similarity). Recruits PSTPIP1 to inflammasomes, and is required for
CC PSTPIP1 oligomerization (By similarity). {ECO:0000250|UniProtKB:O15553,
CC ECO:0000269|PubMed:34471287}.
CC -!- SUBUNIT: Homotrimer. Interacts (via the B box-type zinc finger) with
CC PSTPIP1 (By similarity). Interacts (via the B30.2/SPRY domain) with
CC several components of the inflammasome complex, including CASP1 p20 and
CC p10 subunits, CASP5, PYCARD, NLRP1, NLRP2 AND NLRP3, as well as with
CC unprocessed IL1B; this interaction may lead to autophagic degradation
CC of these proteins (By similarity). Component of the AIM2 PANoptosome
CC complex, a multiprotein complex that drives inflammatory cell death
CC (PANoptosis) (PubMed:34471287). Interacts with NFKBIA and RELA (By
CC similarity). Interacts weakly with VASP and ACTR3 (By similarity).
CC Interacts with active ULK1 (phosphorylated on 'Ser-317') and BECN1
CC simultaneously (By similarity). Also interacts with ATG16L1 (via WD
CC repeats), and with ATG8 family members, including GABARAP, GABARAPL1
CC and, to a lesser extent, GABARAPL2, MAP1LC3A/LC3A and MAP1LC3C/LC3C (By
CC similarity). Interacts with TRIM21 (By similarity). Interacts with
CC TRIM21 (By similarity). Interacts with YWHAB, YWHAE, YWHAG, YWHAH,
CC YWHAQ AND YWHAZ; the interaction is required for the down-regulation of
CC pyrin pro-inflammatory activity (By similarity).
CC {ECO:0000250|UniProtKB:O15553, ECO:0000269|PubMed:34471287}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton
CC {ECO:0000250|UniProtKB:O15553}. Cell projection, ruffle
CC {ECO:0000250|UniProtKB:O15553}. Cell projection, lamellipodium
CC {ECO:0000250|UniProtKB:O15553}. Cytoplasm
CC {ECO:0000250|UniProtKB:O15553}. Cytoplasmic vesicle, autophagosome
CC {ECO:0000250|UniProtKB:O15553}. Nucleus {ECO:0000250|UniProtKB:O15553}.
CC Note=Associated with microtubules and with the filamentous actin of
CC perinuclear filaments and peripheral lamellar ruffles. In pre-apoptotic
CC cells, colocalizes with PYCARD/ASC in large specks (pyroptosomes). In
CC migrating monocytes, strongly polarized at the leading edge of the cell
CC where it colocalizes with polymerizing actin and PYCARD/ASC (By
CC similarity). {ECO:0000250|UniProtKB:O15553}.
CC -!- TISSUE SPECIFICITY: Expressed in spleen peripheral blood granulocytes.
CC Not expressed in lymphocytes, thymus, testis, ovary, heart, brain,
CC lung, liver, kidney and muscle. {ECO:0000269|PubMed:10818206}.
CC -!- DOMAIN: The B box-type zinc finger interacts, possibly
CC intramolecularly, with the pyrin domain; this may be an autoinhibitory
CC mechanism released by PSTPIP1 binding. {ECO:0000250|UniProtKB:O15553}.
CC -!- PTM: Phosphorylation at Ser-241 is required for the interaction with
CC 14-3-3 proteins and down-regulation of pyrin pro-inflammatory activity.
CC {ECO:0000250|UniProtKB:O15553}.
CC -!- PTM: Degraded along with the delivery of its substrates to
CC autolysosomal compartments (at protein level).
CC {ECO:0000250|UniProtKB:O15553}.
CC -!- DISRUPTION PHENOTYPE: Animals are grossly normal, with no obvious
CC changes in thymus, spleen or lymph nodes. In vitro, resident peritoneal
CC macrophage cells show enhanced IL1B and IL18 release in response to
CC inflammatory stimuli. {ECO:0000269|PubMed:23226472}.
CC -!- CAUTION: Lacks the B30.2/SPRY domain found in the human ortholog, thus
CC may have divergent function(s). {ECO:0000305}.
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DR EMBL; AF143409; AAF03766.1; -; mRNA.
DR EMBL; AC139347; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS27907.1; -.
DR RefSeq; NP_062326.2; NM_019453.2.
DR AlphaFoldDB; Q9JJ26; -.
DR SMR; Q9JJ26; -.
DR BioGRID; 207667; 1.
DR ComplexPortal; CPX-4244; Pyrin inflammasome.
DR STRING; 10090.ENSMUSP00000097795; -.
DR iPTMnet; Q9JJ26; -.
DR PhosphoSitePlus; Q9JJ26; -.
DR MaxQB; Q9JJ26; -.
DR PRIDE; Q9JJ26; -.
DR ProteomicsDB; 292191; -.
DR Antibodypedia; 10781; 223 antibodies from 32 providers.
DR DNASU; 54483; -.
DR Ensembl; ENSMUST00000023180; ENSMUSP00000023180; ENSMUSG00000022534.
DR GeneID; 54483; -.
DR KEGG; mmu:54483; -.
DR UCSC; uc007xym.2; mouse.
DR CTD; 4210; -.
DR MGI; MGI:1859396; Mefv.
DR VEuPathDB; HostDB:ENSMUSG00000022534; -.
DR eggNOG; KOG2177; Eukaryota.
DR GeneTree; ENSGT00940000161955; -.
DR HOGENOM; CLU_016050_0_0_1; -.
DR InParanoid; Q9JJ26; -.
DR OMA; CQRHMKQ; -.
DR Reactome; R-MMU-844456; The NLRP3 inflammasome.
DR BioGRID-ORCS; 54483; 4 hits in 71 CRISPR screens.
DR PRO; PR:Q9JJ26; -.
DR Proteomes; UP000000589; Chromosome 16.
DR RNAct; Q9JJ26; protein.
DR Bgee; ENSMUSG00000022534; Expressed in granulocyte and 45 other tissues.
DR ExpressionAtlas; Q9JJ26; baseline and differential.
DR Genevisible; Q9JJ26; MM.
DR GO; GO:0005776; C:autophagosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0031410; C:cytoplasmic vesicle; IEA:UniProtKB-KW.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0061702; C:inflammasome complex; ISO:MGI.
DR GO; GO:0030027; C:lamellipodium; IEA:UniProtKB-SubCell.
DR GO; GO:0005874; C:microtubule; IC:ComplexPortal.
DR GO; GO:0005875; C:microtubule associated complex; ISS:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISO:MGI.
DR GO; GO:0001726; C:ruffle; IEA:UniProtKB-SubCell.
DR GO; GO:0003779; F:actin binding; ISS:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IBA:GO_Central.
DR GO; GO:0008270; F:zinc ion binding; NAS:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; ISS:UniProtKB.
DR GO; GO:0045087; P:innate immune response; IBA:GO_Central.
DR GO; GO:1900016; P:negative regulation of cytokine production involved in inflammatory response; ISS:UniProtKB.
DR GO; GO:0050728; P:negative regulation of inflammatory response; ISO:MGI.
DR GO; GO:0032691; P:negative regulation of interleukin-1 beta production; ISO:MGI.
DR GO; GO:0032695; P:negative regulation of interleukin-12 production; ISO:MGI.
DR GO; GO:0071641; P:negative regulation of macrophage inflammatory protein 1 alpha production; ISO:MGI.
DR GO; GO:1900226; P:negative regulation of NLRP3 inflammasome complex assembly; ISS:UniProtKB.
DR GO; GO:0002221; P:pattern recognition receptor signaling pathway; IC:ComplexPortal.
DR GO; GO:0010508; P:positive regulation of autophagy; ISS:UniProtKB.
DR GO; GO:2001056; P:positive regulation of cysteine-type endopeptidase activity; ISO:MGI.
DR GO; GO:0050729; P:positive regulation of inflammatory response; IDA:ComplexPortal.
DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; IDA:ComplexPortal.
DR GO; GO:0016567; P:protein ubiquitination; IBA:GO_Central.
DR GO; GO:0070269; P:pyroptosis; IC:ComplexPortal.
DR GO; GO:1904270; P:pyroptosome complex assembly; ISS:UniProtKB.
DR GO; GO:0010468; P:regulation of gene expression; IBA:GO_Central.
DR GO; GO:0032651; P:regulation of interleukin-1 beta production; ISS:UniProtKB.
DR GO; GO:0034341; P:response to interferon-gamma; ISS:UniProtKB.
DR Gene3D; 1.10.533.10; -; 1.
DR InterPro; IPR004020; DAPIN.
DR InterPro; IPR011029; DEATH-like_dom_sf.
DR InterPro; IPR028841; Pyrin.
DR InterPro; IPR000315; Znf_B-box.
DR PANTHER; PTHR24103:SF606; PTHR24103:SF606; 2.
DR Pfam; PF02758; PYRIN; 1.
DR Pfam; PF00643; zf-B_box; 1.
DR SMART; SM00336; BBOX; 1.
DR SMART; SM01289; PYRIN; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR PROSITE; PS50824; DAPIN; 1.
DR PROSITE; PS50119; ZF_BBOX; 1.
PE 1: Evidence at protein level;
KW Actin-binding; Cell projection; Coiled coil; Cytoplasm;
KW Cytoplasmic vesicle; Cytoskeleton; Immunity; Inflammatory response;
KW Innate immunity; Metal-binding; Microtubule; Nucleus; Phosphoprotein;
KW Reference proteome; Zinc; Zinc-finger.
FT CHAIN 1..767
FT /note="Pyrin"
FT /id="PRO_0000220365"
FT DOMAIN 1..92
FT /note="Pyrin"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00061,
FT ECO:0000305"
FT ZN_FING 439..481
FT /note="B box-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024"
FT REGION 94..219
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 311..346
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 489..647
FT /note="Required for homotrimerization and induction of
FT pyroptosomes"
FT /evidence="ECO:0000250|UniProtKB:O15553"
FT REGION 697..719
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 481..510
FT /evidence="ECO:0000255"
FT COMPBIAS 124..147
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 149..164
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 165..212
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 311..343
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 444
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024"
FT BINDING 447
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024"
FT BINDING 467
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024"
FT BINDING 473
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024"
FT MOD_RES 241
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O15553"
FT CONFLICT 543
FT /note="E -> G (in Ref. 1; AAF03766)"
FT /evidence="ECO:0000305"
FT CONFLICT 565
FT /note="E -> G (in Ref. 1; AAF03766)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 767 AA; 86409 MW; 828E59E4E8DF5549 CRC64;
MAKTLGDHLL NTLEELLPYD FEKFKFKLQN TSLEKGHSKI PRGHMQMARP VKLASLLITY
YGEEYAVRLT LQILRATNQR QLAEELRKAT GTEHLIEENR VGGSVQSSVE NKAKSVKVPD
VPEGDGTQQN NDESDTLPSS QAEVGKGPQK KSLTKRKDQR GPESLDSQTK PWTRSTAPLY
RRTQGTQSPG DKESTASAQL RRNVSSAGRL QGLYNNAPGR RESKKAEVYV YLPSGKKRPR
SLEITTYSRE GEPPNSEVLP TQEETRNGSL IRMRTATLNG RTTGALEKGT GIPEHSMVLD
EKTFRNMSSK TSLIGEERCP TSWTENGNGS PETTESSGET AGSILSDPEV PLSLCEKPAK
TPEDPASLGQ AACEGRSQDK AVCPLCHTQE GDLRGDTCVQ SSCSCSIAPG DPKASGRCSI
CFQCQGLLAR KSCEAQSPQS LPQCPRHMKQ VLLLFCEDHR EPICLICRLS LEHQGHRVRP
IEEAALEYKE QIREQLERLR EMRGYVEEHR LQGDKKTDDF LKQTEIQKQK ISCPLEKLYQ
LLEKQEQLFV TWLQELSQTI SKVRETYYTR VSLLDEMIEE LEAKQDQPEW DLMQDIGITL
HRAKMMSASE LLDTPPGVKE KLHLLYQKSK SVEKNMQCFS EMLSSEMAFS ASDVAKWEGR
QPSATQVQGL VPTVHLKCDG AHTQDCDVVF YPEREAGGSE PKDYLHPQPA QDTPELHEIH
SRNNKRKFKS FLKWKPSFSR TDWRLRTCCY RDLDQAAAHP NLIFSMI
