ATG4D_MOUSE
ID ATG4D_MOUSE Reviewed; 474 AA.
AC Q8BGV9; Q8C4N9; Q8K0Q2;
DT 15-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 135.
DE RecName: Full=Cysteine protease ATG4D {ECO:0000305};
DE EC=3.4.22.- {ECO:0000250|UniProtKB:Q86TL0};
DE AltName: Full=AUT-like 4 cysteine endopeptidase;
DE AltName: Full=Autophagy-related cysteine endopeptidase 4 {ECO:0000303|PubMed:12446702};
DE Short=Autophagin-4 {ECO:0000303|PubMed:12446702};
DE AltName: Full=Autophagy-related protein 4 homolog D {ECO:0000250|UniProtKB:Q86TL0};
DE Contains:
DE RecName: Full=Cysteine protease ATG4D, mitochondrial {ECO:0000250|UniProtKB:Q86TL0};
GN Name=Atg4d {ECO:0000312|MGI:MGI:2444308}; Synonyms=Apg4d, Autl4;
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;
RN [1]
RP RETRACTED PAPER.
RX PubMed=12446702; DOI=10.1074/jbc.m208247200;
RA Marino G., Uria J.A., Puente X.S., Quesada V., Bordallo J., Lopez-Otin C.;
RT "Human autophagins, a family of cysteine proteinases potentially implicated
RT in cell degradation by autophagy.";
RL J. Biol. Chem. 278:3671-3678(2003).
RN [2]
RP RETRACTION NOTICE OF PUBMED:12446702.
RX PubMed=30808002; DOI=10.1074/jbc.w118.007325;
RA Marino G., Uria J.A., Puente X.S., Quesada V., Bordallo J., Lopez-Otin C.;
RL J. Biol. Chem. 294:1431-1431(2019).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Bone, Cerebellum, and Head;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Colon, and Eye;
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 [5]
RP PROTEIN SEQUENCE OF 13-25, AND IDENTIFICATION BY MASS SPECTROMETRY.
RC STRAIN=OF1; TISSUE=Hippocampus;
RA Lubec G., Sunyer B., Chen W.-Q.;
RL Submitted (JAN-2009) to UniProtKB.
RN [6]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=33795848; DOI=10.1038/s41418-021-00776-1;
RA Tamargo-Gomez I., Martinez-Garcia G.G., Suarez M.F., Rey V., Fueyo A.,
RA Codina-Martinez H., Bretones G., Caravia X.M., Morel E., Dupont N.,
RA Cabo R., Tomas-Zapico C., Souquere S., Pierron G., Codogno P.,
RA Lopez-Otin C., Fernandez A.F., Marino G.;
RT "ATG4D is the main ATG8 delipidating enzyme in mammalian cells and protects
RT against cerebellar neurodegeneration.";
RL Cell Death Differ. 28:2651-2672(2021).
RN [7]
RP MUTAGENESIS OF ARG-125.
RX PubMed=33988247; DOI=10.1111/cge.13995;
RA Sha Y., Liu W., Wei X., Zhu X., Tang B., Zhang X., Yang X., Wang Y.,
RA Wang X.;
RT "Pathogenic variants of ATG4D in infertile men with non-obstructive
RT azoospermia identified using whole-exome sequencing.";
RL Clin. Genet. 100:280-291(2021).
CC -!- FUNCTION: [Cysteine protease ATG4D]: Cysteine protease that plays a key
CC role in autophagy by mediating both proteolytic activation and
CC delipidation of ATG8 family proteins (PubMed:33795848). The protease
CC activity is required for proteolytic activation of ATG8 family
CC proteins: cleaves the C-terminal amino acid of ATG8 proteins MAP1LC3
CC and GABARAPL2, to reveal a C-terminal glycine (By similarity). Exposure
CC of the glycine at the C-terminus is essential for ATG8 proteins
CC conjugation to phosphatidylethanolamine (PE) and insertion to
CC membranes, which is necessary for autophagy (By similarity). In
CC addition to the protease activity, also mediates delipidation of ATG8
CC family proteins (PubMed:33795848). Catalyzes delipidation of PE-
CC conjugated forms of ATG8 proteins during macroautophagy
CC (PubMed:33795848). Also involved in non-canonical autophagy, a parallel
CC pathway involving conjugation of ATG8 proteins to single membranes at
CC endolysosomal compartments, by catalyzing delipidation of ATG8 proteins
CC conjugated to phosphatidylserine (PS) (By similarity). ATG4D plays a
CC role in the autophagy-mediated neuronal homeostasis in the central
CC nervous system (PubMed:33795848). Compared to other members of the
CC family (ATG4A, ATG4B or ATG4C), constitutes the major protein for the
CC delipidation activity, while it promotes weak proteolytic activation of
CC ATG8 proteins (PubMed:33795848). Involved in phagophore growth during
CC mitophagy independently of its protease activity and of ATG8 proteins:
CC acts by regulating ATG9A trafficking to mitochondria and promoting
CC phagophore-endoplasmic reticulum contacts during the lipid transfer
CC phase of mitophagy (By similarity). {ECO:0000250|UniProtKB:Q86TL0,
CC ECO:0000250|UniProtKB:Q9Y4P1, ECO:0000269|PubMed:33795848}.
CC -!- FUNCTION: [Cysteine protease ATG4D, mitochondrial]: Plays a role as an
CC autophagy regulator that links mitochondrial dysfunction with
CC apoptosis. The mitochondrial import of ATG4D during cellular stress and
CC differentiation may play important roles in the regulation of
CC mitochondrial physiology, ROS, mitophagy and cell viability.
CC {ECO:0000250|UniProtKB:Q86TL0}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=[protein]-C-terminal L-amino acid-glycyl-
CC phosphatidylethanolamide + H2O = [protein]-C-terminal L-amino acid-
CC glycine + a 1,2-diacyl-sn-glycero-3-phosphoethanolamine;
CC Xref=Rhea:RHEA:67548, Rhea:RHEA-COMP:17323, Rhea:RHEA-COMP:17324,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:64612, ChEBI:CHEBI:172940,
CC ChEBI:CHEBI:172941; Evidence={ECO:0000250|UniProtKB:Q86TL0};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:67549;
CC Evidence={ECO:0000250|UniProtKB:Q86TL0};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=[protein]-C-terminal L-amino acid-glycyl-phosphatidylserine +
CC H2O = [protein]-C-terminal L-amino acid-glycine + a 1,2-diacyl-sn-
CC glycero-3-phospho-L-serine; Xref=Rhea:RHEA:67576, Rhea:RHEA-
CC COMP:17324, Rhea:RHEA-COMP:17326, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:57262, ChEBI:CHEBI:172940, ChEBI:CHEBI:172942;
CC Evidence={ECO:0000250|UniProtKB:Q86TL0};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:67577;
CC Evidence={ECO:0000250|UniProtKB:Q86TL0};
CC -!- ACTIVITY REGULATION: Inhibited by N-ethylmaleimide.
CC {ECO:0000250|UniProtKB:Q86TL0}.
CC -!- SUBCELLULAR LOCATION: [Cysteine protease ATG4D]: Cytoplasm
CC {ECO:0000250|UniProtKB:Q86TL0}.
CC -!- SUBCELLULAR LOCATION: [Cysteine protease ATG4D, mitochondrial]:
CC Cytoplasm {ECO:0000250|UniProtKB:Q86TL0}. Mitochondrion matrix
CC {ECO:0000250|UniProtKB:Q86TL0}. Note=Imported into mitochondrial matrix
CC after cleavage by CASP3 during oxidative stress and cell death.
CC {ECO:0000250|UniProtKB:Q86TL0}.
CC -!- DOMAIN: The cryptic mitochondrial transit peptide is revealed after
CC cleavage by caspase upon oxidative stress and cell death. It acts then
CC as a functional transit peptide, and allows the import of the cleaved
CC protein into the mitochondria. {ECO:0000250|UniProtKB:Q86TL0}.
CC -!- PTM: Cleaved by CASP3 during apoptosis which leads to increased
CC activity. The cleavage by CASP3 reveals a cryptic mitochondrial
CC targeting sequence immediately downstream of their canonical caspase
CC cleavage sites which leads to mitochondrial import of the protein.
CC {ECO:0000250|UniProtKB:Q86TL0}.
CC -!- DISRUPTION PHENOTYPE: Mice develop normally and are born at the
CC expected Mendelian ration (PubMed:33795848). Cells display accumulation
CC of lipidated forms of ATG8 family proteins, affecting autophagosome
CC number and size without significantly altering autophagic flux
CC (PubMed:33795848). Mice show cerebellar neurodegeneration and impaired
CC motor coordination, whose severity increases with age
CC (PubMed:33795848). {ECO:0000269|PubMed:33795848}.
CC -!- SIMILARITY: Belongs to the peptidase C54 family. {ECO:0000305}.
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DR EMBL; AJ312333; CAC85952.1; -; Genomic_DNA.
DR EMBL; AK036571; BAC29484.1; -; mRNA.
DR EMBL; AK081605; BAC38269.1; -; mRNA.
DR EMBL; AK081002; BAC38110.1; -; mRNA.
DR EMBL; BC030861; AAH30861.1; -; mRNA.
DR EMBL; BC069851; AAH69851.1; -; mRNA.
DR CCDS; CCDS22899.1; -.
DR RefSeq; NP_705811.8; NM_153583.10.
DR AlphaFoldDB; Q8BGV9; -.
DR SMR; Q8BGV9; -.
DR STRING; 10090.ENSMUSP00000068450; -.
DR MEROPS; C54.005; -.
DR iPTMnet; Q8BGV9; -.
DR PhosphoSitePlus; Q8BGV9; -.
DR MaxQB; Q8BGV9; -.
DR PaxDb; Q8BGV9; -.
DR PRIDE; Q8BGV9; -.
DR ProteomicsDB; 265164; -.
DR Antibodypedia; 25362; 639 antibodies from 37 providers.
DR DNASU; 235040; -.
DR Ensembl; ENSMUST00000065005; ENSMUSP00000068450; ENSMUSG00000002820.
DR GeneID; 235040; -.
DR KEGG; mmu:235040; -.
DR UCSC; uc009okt.2; mouse.
DR CTD; 84971; -.
DR MGI; MGI:2444308; Atg4d.
DR VEuPathDB; HostDB:ENSMUSG00000002820; -.
DR eggNOG; KOG2674; Eukaryota.
DR GeneTree; ENSGT00530000063000; -.
DR HOGENOM; CLU_021259_3_2_1; -.
DR InParanoid; Q8BGV9; -.
DR OMA; MPRDWAW; -.
DR OrthoDB; 431748at2759; -.
DR PhylomeDB; Q8BGV9; -.
DR TreeFam; TF314847; -.
DR Reactome; R-MMU-1632852; Macroautophagy.
DR BioGRID-ORCS; 235040; 4 hits in 72 CRISPR screens.
DR ChiTaRS; Atg4d; mouse.
DR PRO; PR:Q8BGV9; -.
DR Proteomes; UP000000589; Chromosome 9.
DR RNAct; Q8BGV9; protein.
DR Bgee; ENSMUSG00000002820; Expressed in granulocyte and 177 other tissues.
DR ExpressionAtlas; Q8BGV9; baseline and differential.
DR Genevisible; Q8BGV9; MM.
DR GO; GO:0005759; C:mitochondrial matrix; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0008234; F:cysteine-type peptidase activity; ISS:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0006914; P:autophagy; ISS:UniProtKB.
DR GO; GO:0000423; P:mitophagy; ISS:UniProtKB.
DR GO; GO:0051697; P:protein delipidation; IMP:UniProtKB.
DR GO; GO:0034497; P:protein localization to phagophore assembly site; ISS:UniProtKB.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0006508; P:proteolysis; ISO:MGI.
DR InterPro; IPR038765; Papain-like_cys_pep_sf.
DR InterPro; IPR005078; Peptidase_C54.
DR PANTHER; PTHR22624; PTHR22624; 1.
DR Pfam; PF03416; Peptidase_C54; 1.
DR SUPFAM; SSF54001; SSF54001; 1.
PE 1: Evidence at protein level;
KW Apoptosis; Autophagy; Cytoplasm; Direct protein sequencing; Hydrolase;
KW Mitochondrion; Phosphoprotein; Protease; Protein transport;
KW Reference proteome; Thiol protease; Transport; Ubl conjugation pathway.
FT CHAIN 1..474
FT /note="Cysteine protease ATG4D"
FT /id="PRO_0000215854"
FT CHAIN 64..474
FT /note="Cysteine protease ATG4D, mitochondrial"
FT /evidence="ECO:0000250|UniProtKB:Q86TL0"
FT /id="PRO_0000423409"
FT REGION 1..60
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 64..103
FT /note="Cryptic mitochondrial signal peptide"
FT /evidence="ECO:0000250|UniProtKB:Q86TL0"
FT REGION 175..198
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 16..30
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 144
FT /note="Nucleophile"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT ACT_SITE 356
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT ACT_SITE 358
FT /evidence="ECO:0000250|UniProtKB:Q9Y4P1"
FT SITE 63..64
FT /note="Cleavage; by CASP3"
FT /evidence="ECO:0000250|UniProtKB:Q86TL0"
FT MOD_RES 467
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q86TL0"
FT MUTAGEN 125
FT /note="R->L: Increased programmed cell death in
FT spermatogenic cells; decreased expression of MAP1LC3B."
FT /evidence="ECO:0000269|PubMed:33988247"
FT CONFLICT 26
FT /note="R -> Q (in Ref. 3; BAC38269)"
FT /evidence="ECO:0000305"
FT CONFLICT 111
FT /note="R -> Q (in Ref. 4; AAH30861)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 474 AA; 52910 MW; 699C1472A562FB20 CRC64;
MNSVSPAAAQ YRSGSSEDAR RADCRRPRGQ TRIPDPSNLG PSGSGVAALG SSGTDPAEPD
EVDKFKAKFL TAWNNVKYGW AVKSRTSFSK ISTVHLCGRC YHFEGEGDIQ RFQRDFVSRL
WLTYRRDFPP LAGGSLTSDC GWGCMLRSGQ MMLAQGLLLH FLPRDWRWVE GTGLASSEMP
GPASPSRCRG PGRRGPPRWT QGALEMEQDR WHRRIVSWFA DHPRAPFGLH RLVELGRSSG
KKAGDWYGPS VVAHILRKAV ESCSEVSRLV VYVSQDCTVY KADVARLLSW PDPTAEWKSV
VILVPVRLGG ETLNPVYVPC VKELLRSELC LGIMGGKPRH SLYFIGYQDD FLLYLDPHYC
QPTVDVSQPS FPLESFHCTS PRKMAFAKMD PSCTVGFYAG NRKEFETLCS ELMRILSSSS
VTERYPMFTV AEGHAQDHSL DALCTQLSQP TLRLPCTGRL LKAKRPSSED FVFL
