NPL41_CAEEL
ID NPL41_CAEEL Reviewed; 529 AA.
AC H2KYU6; Q95QZ7;
DT 12-SEP-2018, integrated into UniProtKB/Swiss-Prot.
DT 21-MAR-2012, sequence version 1.
DT 25-MAY-2022, entry version 70.
DE RecName: Full=Nuclear protein localization protein 4 homolog 1 {ECO:0000312|WormBase:F59E12.4b};
GN Name=npl-4.1 {ECO:0000312|WormBase:F59E12.4b};
GN ORFNames=F59E12.4 {ECO:0000312|WormBase:F59E12.4a};
OS Caenorhabditis elegans.
OC Eukaryota; Metazoa; Ecdysozoa; Nematoda; Chromadorea; Rhabditida;
OC Rhabditina; Rhabditomorpha; Rhabditoidea; Rhabditidae; Peloderinae;
OC Caenorhabditis.
OX NCBI_TaxID=6239 {ECO:0000312|Proteomes:UP000001940};
RN [1] {ECO:0000312|Proteomes:UP000001940}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Bristol N2 {ECO:0000312|Proteomes:UP000001940};
RX PubMed=9851916; DOI=10.1126/science.282.5396.2012;
RG The C. elegans sequencing consortium;
RT "Genome sequence of the nematode C. elegans: a platform for investigating
RT biology.";
RL Science 282:2012-2018(1998).
RN [2] {ECO:0000305}
RP FUNCTION, INTERACTION WITH UFD-1, AND DISRUPTION PHENOTYPE.
RX PubMed=16647269; DOI=10.1016/j.jsb.2006.02.015;
RA Mouysset J., Kaehler C., Hoppe T.;
RT "A conserved role of Caenorhabditis elegans CDC-48 in ER-associated protein
RT degradation.";
RL J. Struct. Biol. 156:41-49(2006).
RN [3] {ECO:0000305}
RP FUNCTION, SUBCELLULAR LOCATION, AND DISRUPTION PHENOTYPE.
RX PubMed=18728180; DOI=10.1073/pnas.0805944105;
RA Mouysset J., Deichsel A., Moser S., Hoege C., Hyman A.A., Gartner A.,
RA Hoppe T.;
RT "Cell cycle progression requires the CDC-48UFD-1/NPL-4 complex for
RT efficient DNA replication.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:12879-12884(2008).
RN [4] {ECO:0000305}
RP INTERACTION WITH ELC-1.
RX PubMed=19773360; DOI=10.1242/jcs.052415;
RA Sasagawa Y., Otani M., Higashitani N., Higashitani A., Sato K., Ogura T.,
RA Yamanaka K.;
RT "Caenorhabditis elegans p97 controls germline-specific sex determination by
RT controlling the TRA-1 level in a CUL-2-dependent manner.";
RL J. Cell Sci. 122:3663-3672(2009).
RN [5] {ECO:0000305}
RP IDENTIFICATION IN A COMPLEX WITH UBXN-3; UFD-1 AND CDC-48.1, AND
RP INTERACTION WITH UBXN-3 AND UFD-1.
RX PubMed=20977550; DOI=10.1111/j.1365-2443.2010.01454.x;
RA Sasagawa Y., Yamanaka K., Saito-Sasagawa Y., Ogura T.;
RT "Caenorhabditis elegans UBX cofactors for CDC-48/p97 control
RT spermatogenesis.";
RL Genes Cells 15:1201-1215(2010).
RN [6] {ECO:0000305}
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=21981920; DOI=10.1016/j.molcel.2011.08.028;
RA Franz A., Orth M., Pirson P.A., Sonneville R., Blow J.J., Gartner A.,
RA Stemmann O., Hoppe T.;
RT "CDC-48/p97 coordinates CDT-1 degradation with GINS chromatin dissociation
RT to ensure faithful DNA replication.";
RL Mol. Cell 44:85-96(2011).
RN [7] {ECO:0000305}
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=22768338; DOI=10.1371/journal.pone.0040145;
RA Miedel M.T., Graf N.J., Stephen K.E., Long O.S., Pak S.C., Perlmutter D.H.,
RA Silverman G.A., Luke C.J.;
RT "A pro-cathepsin L mutant is a luminal substrate for endoplasmic-reticulum-
RT associated degradation in C. elegans.";
RL PLoS ONE 7:E40145-E40145(2012).
RN [8] {ECO:0000305}
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=26842564; DOI=10.1038/ncomms10612;
RA Franz A., Pirson P.A., Pilger D., Halder S., Achuthankutty D., Kashkar H.,
RA Ramadan K., Hoppe T.;
RT "Chromatin-associated degradation is defined by UBXN-3/FAF1 to safeguard
RT DNA replication fork progression.";
RL Nat. Commun. 7:10612-10612(2016).
RN [9] {ECO:0000305}
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=28368371; DOI=10.1038/ncb3500;
RA Sonneville R., Moreno S.P., Knebel A., Johnson C., Hastie C.J., Gartner A.,
RA Gambus A., Labib K.;
RT "CUL-2LRR-1 and UBXN-3 drive replisome disassembly during DNA replication
RT termination and mitosis.";
RL Nat. Cell Biol. 19:468-479(2017).
CC -!- FUNCTION: In association with ufd-1 and ATPase cdc-48.1 and/or cdc-
CC 48.2, involved in the cytoplasmic elimination of misfolded proteins
CC exported from the ER (PubMed:16647269, PubMed:22768338). This pathway,
CC known as ERAD, prevents the activation of the unfolded protein response
CC (UPR) caused by the accumulation of misfolded proteins in the ER
CC (PubMed:16647269, PubMed:22768338). During S phase and in association
CC with ufd-1, cdc-48.1 and/or cdc-48.2 and ubxn-3, ensures the
CC degradation of DNA licensing factor cdt-1 after the initiation of DNA
CC replication and thus the disassembly of the DNA replication CGM
CC helicase complex by promoting the dissociation from chromatin of
CC several of its components including cdc-45 and sld-5 (PubMed:18728180,
CC PubMed:21981920, PubMed:26842564, PubMed:28368371). Regulates ubxn-3
CC nuclear localization during S phase (PubMed:26842564).
CC {ECO:0000269|PubMed:16647269, ECO:0000269|PubMed:18728180,
CC ECO:0000269|PubMed:21981920, ECO:0000269|PubMed:22768338,
CC ECO:0000269|PubMed:26842564, ECO:0000269|PubMed:28368371}.
CC -!- SUBUNIT: Forms a complex composed of ubxn-3, ufd-1, npl-4.1 and cdc-
CC 48.1; within the complex, interacts with ufd-1 and ubxn-3
CC (PubMed:20977550). Interacts with ufd-1 (PubMed:16647269). Interacts
CC with elc-1/elongin C; the interaction may mediate the interaction
CC between the npl-4-ufd-1-cdc-48 complex and the E3 ubiquitin ligase cul-
CC 2 complex (PubMed:19773360). {ECO:0000269|PubMed:16647269,
CC ECO:0000269|PubMed:19773360, ECO:0000269|PubMed:20977550}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:18728180}. Nucleus
CC {ECO:0000269|PubMed:18728180}. Note=Localizes to the cytoplasm during
CC mitosis. Nuclear localization upon nuclear membrane re-assembly is cdc-
CC 48-dependent. {ECO:0000269|PubMed:18728180}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=b {ECO:0000312|WormBase:F59E12.4b};
CC IsoId=H2KYU6-1; Sequence=Displayed;
CC Name=a {ECO:0000312|WormBase:F59E12.4b};
CC IsoId=H2KYU6-2; Sequence=VSP_059819;
CC -!- DISRUPTION PHENOTYPE: Simultaneous RNAi-mediated knockdown of npl-4.1
CC and npl-4.2 causes embryonic lethality (PubMed:16647269,
CC PubMed:26842564). In embryos, DNA replication is partially impaired
CC causing a delay in S phase progression in P0, AB and P1 cells;
CC simultaneous RNAi-mediated knockdown of DNA replication checkpoint
CC kinases chk-1 or atl-1 suppresses the delay in S phase
CC (PubMed:18728180, PubMed:26842564). During S phase, prevents DNA
CC replication licensing factor cdt-1 down-regulation and causes cdt-1
CC accumulation on mitotic chromosomes (PubMed:21981920). Impairs
CC dissociation from the chromatin of components of the DNA replication
CC machinery, including cdc-45, GINS complex component sld-5 and CMG
CC helicase component mcm-3, resulting in their persistent association
CC with chromatin throughout embryonic mitosis (PubMed:21981920,
CC PubMed:26842564, PubMed:28368371). Abnormal ubxn-3 localization into
CC punctate structures in the nucleus (PubMed:26842564). Reduces ufd-1
CC expression in embryos (PubMed:21981920, PubMed:26842564). Simultaneous
CC RNAi-mediated knockdown of npl-4.1 and npl-4.2 in adults causes a
CC proliferation arrest of mitotic germline cells in the gonad with
CC formation of rad-51 foci on chromatin (PubMed:18728180). Induces the
CC unfolded protein response and increases sensitivity to tunicamycin-
CC induced ER stress (PubMed:16647269). Causes accumulation of misfolded
CC protein cpl-1 in the ER (PubMed:22768338).
CC {ECO:0000269|PubMed:16647269, ECO:0000269|PubMed:18728180,
CC ECO:0000269|PubMed:21981920, ECO:0000269|PubMed:22768338,
CC ECO:0000269|PubMed:26842564}.
CC -!- SIMILARITY: Belongs to the NPL4 family. {ECO:0000305}.
CC -!- CAUTION: There is another gene, npl-4.2, which has a 99% identical
CC sequence making it difficult to identify the specific function for each
CC protein. {ECO:0000305}.
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DR EMBL; BX284602; CCD64968.1; -; Genomic_DNA.
DR EMBL; BX284602; CCD64969.1; -; Genomic_DNA.
DR RefSeq; NP_495096.1; NM_062695.4. [H2KYU6-1]
DR RefSeq; NP_495097.1; NM_062696.4.
DR AlphaFoldDB; H2KYU6; -.
DR SMR; H2KYU6; -.
DR DIP; DIP-25816N; -.
DR IntAct; H2KYU6; 2.
DR STRING; 6239.F59E12.4b; -.
DR EPD; H2KYU6; -.
DR PaxDb; H2KYU6; -.
DR PeptideAtlas; H2KYU6; -.
DR EnsemblMetazoa; F59E12.4a.1; F59E12.4a.1; WBGene00019120. [H2KYU6-2]
DR EnsemblMetazoa; F59E12.4b.1; F59E12.4b.1; WBGene00019120. [H2KYU6-1]
DR GeneID; 173952; -.
DR KEGG; cel:CELE_F59E12.4; -.
DR UCSC; F59E12.4a; c. elegans.
DR CTD; 173952; -.
DR WormBase; F59E12.4a; CE28572; WBGene00019120; npl-4.1. [H2KYU6-2]
DR WormBase; F59E12.4b; CE28573; WBGene00019120; npl-4.1. [H2KYU6-1]
DR eggNOG; KOG2834; Eukaryota.
DR GeneTree; ENSGT00390000018731; -.
DR HOGENOM; CLU_017172_2_0_1; -.
DR InParanoid; H2KYU6; -.
DR OMA; NQFIESW; -.
DR OrthoDB; 1106766at2759; -.
DR PhylomeDB; H2KYU6; -.
DR PRO; PR:H2KYU6; -.
DR Proteomes; UP000001940; Chromosome II.
DR Bgee; WBGene00019120; Expressed in adult organism and 3 other tissues.
DR GO; GO:0005634; C:nucleus; IDA:WormBase.
DR GO; GO:0034098; C:VCP-NPL4-UFD1 AAA ATPase complex; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0044877; F:protein-containing complex binding; IDA:UniProtKB.
DR GO; GO:0043130; F:ubiquitin binding; IBA:GO_Central.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IBA:GO_Central.
DR GO; GO:1900182; P:positive regulation of protein localization to nucleus; IMP:UniProtKB.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IBA:GO_Central.
DR CDD; cd08061; MPN_NPL4; 1.
DR InterPro; IPR037518; MPN.
DR InterPro; IPR016563; Npl4.
DR InterPro; IPR007717; NPL4_C.
DR InterPro; IPR007716; NPL4_Zn-bd_put.
DR InterPro; IPR001876; Znf_RanBP2.
DR InterPro; IPR036443; Znf_RanBP2_sf.
DR PANTHER; PTHR12710; PTHR12710; 1.
DR Pfam; PF05021; NPL4; 1.
DR Pfam; PF05020; zf-NPL4; 1.
DR PIRSF; PIRSF010052; Polyub_prc_Npl4; 1.
DR SMART; SM00547; ZnF_RBZ; 1.
DR SUPFAM; SSF90209; SSF90209; 1.
DR PROSITE; PS50249; MPN; 1.
DR PROSITE; PS01358; ZF_RANBP2_1; 1.
DR PROSITE; PS50199; ZF_RANBP2_2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Chaperone; Cytoplasm; Metal-binding; Nucleus;
KW Reference proteome; Zinc; Zinc-finger.
FT CHAIN 1..529
FT /note="Nuclear protein localization protein 4 homolog 1"
FT /id="PRO_0000445084"
FT DOMAIN 129..266
FT /note="MPN"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01182"
FT ZN_FING 499..529
FT /note="RanBP2-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00322"
FT VAR_SEQ 479..480
FT /note="Missing (in isoform a)"
FT /evidence="ECO:0000305"
FT /id="VSP_059819"
SQ SEQUENCE 529 AA; 59579 MW; F1358139A3ED1D47 CRC64;
MVLEVPQTER VNDVDVFLST QDGQIQRPKG PNCRHPVRQK CTNCLPVDPF DEEYLKEKDI
KHMSFHAHVR KLLGSQGKGT TLKKPLENFR CSLKPNCDAH KPFPKGICTK CKPQVVTLNR
QKFRHVDNIQ IENQELVNQF LDYWRLSGHQ RVGFLIGQYQ PHLEVPLGIK ATVAAIYEPP
QHCREDGIEF LEDKNQKTID NLLEMLGLQR VGWIFTDCWT ANSAEGTVHY TRHKDSFFLS
AEECITAAML QNQHPNITEY SMDRHYGSKF VTVVASGDES MHVNFHGYQV SNQCAAMVEA
DILCPTLYTP ELAYVRETPL SEEHYITDVQ FSMKNEYGAE VMKNGRPLPV EYLLVDVPAG
MPKEPHYTFH VGTSNKSKSA KFNVENRQAI GQLQGGANLI QYSSEFSKNQ FLEQATNFHF
LLYLVTNDQV QISDEWMKRL CDAVKAQDRG TAMEWAQECE DWHQLMALAH ANGGSGNDVS
DIPVIPNGDP FSGSSSGGSG GAVWNCGHCT FQNEAARQDC SMCGLPAAD
