Pexophagy (Homo sapiens)

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15, 8, 104467925, 8, 1031, 2222peroxisomal matrixcytosolATMdimer:Ub-p-PEX5:SQSTM1:NBR1:MAP1LC3BATM ATM EPAS1ATM Ub-p-PEX5 UBB(77-152) ATM MAP1LC3B UBC(229-304) Ub-p-PEX5 ATM dimer:p-PEX5ATM Ub-p-PEX5 NBR1SQSTM1 ATMdimer:Ub-p-PEX5:SQSTM1UBB(1-76) USP30NBR1 MAP1LC3B UBA52(1-76) SQSTM1 ATM UBC(153-228) ATM UBC(609-684) ATMdimer:Ub-p-PEX5:SQSTM1:MAP1LC3BMAP1LC3B PEX5 NBR1:MAP1LC3BATM dimer:Ub-p-PEX5NBR1 UBC(381-456) USP30 UBC(533-608) SQSTM1SQSTM1 UBC(457-532) MAP1LC3BPEX5ATM:PEX5UBB(153-228) ATM UBC(77-152) Ub-p-PEX5 PEX5 ATMdimer:Ub-p-PEX5:SQSTM1:NBR1H2OSQSTM1 ATMUb-p-PEX5 Ub-p-PEX5 ATMdimer:Ub-p-PEX5:USP30ATM:PEX5NBR1 NBR1RPS27A(1-76) ATM dimer:PEX5UbUBC(1-76) UBC(305-380) ROSPEX5 ATM ATM p-PEX5 ATM


Description

Peroxisomes are cytosolic organelles involved in the catabolism of branched and long-chain fatty acids and in the reduction of reactive oxygen species (ROS). Peroxisomes homeostasis is critical to maintain ROS levels. Consequently, it is important to eliminate dysfunctional peroxisomes. The degradation of peroxisomes by autophagy is known as pexophagy (Katarzyna ZR et al. 2016). Pexophagy can be triggered by a shift in nutrient conditions. View original pathway at Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 9664873
Reactome-version 
Reactome version: 74
Reactome Author 
Reactome Author: Varusai, Thawfeek

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Bibliography

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  1. Zhang J, Tripathi DN, Jing J, Alexander A, Kim J, Powell RT, Dere R, Tait-Mulder J, Lee JH, Paull TT, Pandita RK, Charaka VK, Pandita TK, Kastan MB, Walker CL.; ''ATM functions at the peroxisome to induce pexophagy in response to ROS.''; PubMed Europe PMC Scholia
  2. Kirkin V, Lamark T, Johansen T, Dikic I.; ''NBR1 cooperates with p62 in selective autophagy of ubiquitinated targets.''; PubMed Europe PMC Scholia
  3. Marcassa E, Kallinos A, Jardine J, Rusilowicz-Jones EV, Clague MJ, Urbé S.; ''New aspects of USP30 biology in the regulation of pexophagy.''; PubMed Europe PMC Scholia
  4. Walter KM, Schönenberger MJ, Trötzmüller M, Horn M, Elsässer HP, Moser AB, Lucas MS, Schwarz T, Gerber PA, Faust PL, Moch H, Köfeler HC, Krek W, Kovacs WJ.; ''Hif-2α promotes degradation of mammalian peroxisomes by selective autophagy.''; PubMed Europe PMC Scholia
  5. Kirkin V, Lamark T, Sou YS, Bjørkøy G, Nunn JL, Bruun JA, Shvets E, McEwan DG, Clausen TH, Wild P, Bilusic I, Theurillat JP, Øvervatn A, Ishii T, Elazar Z, Komatsu M, Dikic I, Johansen T.; ''A role for NBR1 in autophagosomal degradation of ubiquitinated substrates.''; PubMed Europe PMC Scholia
  6. Riccio V, Demers N, Hua R, Vissa M, Cheng DT, Strilchuk AW, Wang Y, McQuibban GA, Kim PK.; ''Deubiquitinating enzyme USP30 maintains basal peroxisome abundance by regulating pexophagy.''; PubMed Europe PMC Scholia
  7. Riccio V, McQuibban GA, Kim PK.; ''USP30: protector of peroxisomes and mitochondria.''; PubMed Europe PMC Scholia
  8. Guo Z, Kozlov S, Lavin MF, Person MD, Paull TT.; ''ATM activation by oxidative stress.''; PubMed Europe PMC Scholia
  9. Zientara-Rytter K, Subramani S.; ''Autophagic degradation of peroxisomes in mammals.''; PubMed Europe PMC Scholia
  10. Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, Øvervatn A, Bjørkøy G, Johansen T.; ''p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy.''; PubMed Europe PMC Scholia

History

CompareRevisionActionTimeUserComment
114964view16:49, 25 January 2021ReactomeTeamReactome version 75
113408view11:48, 2 November 2020ReactomeTeamReactome version 74
112825view18:29, 9 October 2020DeSlOntology Term : 'homeostasis pathway' added !
112772view16:17, 9 October 2020ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ATM dimer:Ub-p-PEX5:SQSTM1:MAP1LC3BComplexR-HSA-9665167 (Reactome)
ATM dimer:Ub-p-PEX5:SQSTM1:NBR1:MAP1LC3BComplexR-HSA-9665166 (Reactome)
ATM dimer:Ub-p-PEX5:SQSTM1:NBR1ComplexR-HSA-9665165 (Reactome)
ATM dimer:Ub-p-PEX5:SQSTM1ComplexR-HSA-9665168 (Reactome)
ATM dimer:Ub-p-PEX5:USP30ComplexR-HSA-9674136 (Reactome)
ATM ProteinQ13315 (Uniprot-TrEMBL)
ATM dimer:PEX5ComplexR-HSA-9665185 (Reactome)
ATM dimer:Ub-p-PEX5ComplexR-HSA-9665179 (Reactome)
ATM dimer:p-PEX5ComplexR-HSA-9665178 (Reactome)
ATM:PEX5ComplexR-HSA-9665170 (Reactome)
ATM:PEX5ComplexR-HSA-9665176 (Reactome)
ATMProteinQ13315 (Uniprot-TrEMBL)
EPAS1ProteinQ99814 (Uniprot-TrEMBL)
H2OMetaboliteCHEBI:15377 (ChEBI)
MAP1LC3B ProteinQ9GZQ8 (Uniprot-TrEMBL)
MAP1LC3BProteinQ9GZQ8 (Uniprot-TrEMBL)
NBR1 ProteinQ14596 (Uniprot-TrEMBL)
NBR1:MAP1LC3BComplexR-HSA-9665173 (Reactome)
NBR1ProteinQ14596 (Uniprot-TrEMBL)
PEX5 ProteinP50542 (Uniprot-TrEMBL)
PEX5ProteinP50542 (Uniprot-TrEMBL)
ROSMetaboliteCHEBI:26523 (ChEBI)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
SQSTM1 ProteinQ13501 (Uniprot-TrEMBL)
SQSTM1ProteinQ13501 (Uniprot-TrEMBL)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
USP30 ProteinQ70CQ3 (Uniprot-TrEMBL)
USP30ProteinQ70CQ3 (Uniprot-TrEMBL)
Ub-p-PEX5 ProteinP50542 (Uniprot-TrEMBL)
UbComplexR-HSA-113595 (Reactome)
p-PEX5 ProteinP50542 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ATM dimer:Ub-p-PEX5:SQSTM1:MAP1LC3BArrowR-HSA-9664855 (Reactome)
ATM dimer:Ub-p-PEX5:SQSTM1:NBR1:MAP1LC3BArrowR-HSA-9664880 (Reactome)
ATM dimer:Ub-p-PEX5:SQSTM1:NBR1ArrowR-HSA-9664881 (Reactome)
ATM dimer:Ub-p-PEX5:SQSTM1:NBR1R-HSA-9664880 (Reactome)
ATM dimer:Ub-p-PEX5:SQSTM1ArrowR-HSA-9664892 (Reactome)
ATM dimer:Ub-p-PEX5:SQSTM1R-HSA-9664855 (Reactome)
ATM dimer:Ub-p-PEX5:SQSTM1R-HSA-9664881 (Reactome)
ATM dimer:Ub-p-PEX5:USP30ArrowR-HSA-9674131 (Reactome)
ATM dimer:Ub-p-PEX5:USP30R-HSA-9674127 (Reactome)
ATM dimer:Ub-p-PEX5:USP30mim-catalysisR-HSA-9674127 (Reactome)
ATM dimer:PEX5ArrowR-HSA-9664879 (Reactome)
ATM dimer:PEX5R-HSA-9664862 (Reactome)
ATM dimer:Ub-p-PEX5ArrowR-HSA-9664888 (Reactome)
ATM dimer:Ub-p-PEX5R-HSA-9664892 (Reactome)
ATM dimer:Ub-p-PEX5R-HSA-9674131 (Reactome)
ATM dimer:p-PEX5ArrowR-HSA-9664862 (Reactome)
ATM dimer:p-PEX5ArrowR-HSA-9674127 (Reactome)
ATM dimer:p-PEX5R-HSA-9664888 (Reactome)
ATM:PEX5ArrowR-HSA-9664850 (Reactome)
ATM:PEX5ArrowR-HSA-9664883 (Reactome)
ATM:PEX5R-HSA-9664879 (Reactome)
ATM:PEX5R-HSA-9664883 (Reactome)
ATMR-HSA-9664850 (Reactome)
ATMR-HSA-9664879 (Reactome)
EPAS1ArrowR-HSA-9664871 (Reactome)
H2OR-HSA-9674127 (Reactome)
MAP1LC3BR-HSA-9664855 (Reactome)
MAP1LC3BR-HSA-9664867 (Reactome)
MAP1LC3BR-HSA-9664880 (Reactome)
NBR1:MAP1LC3BArrowR-HSA-9664867 (Reactome)
NBR1ArrowR-HSA-9664871 (Reactome)
NBR1R-HSA-9664867 (Reactome)
NBR1R-HSA-9664871 (Reactome)
NBR1R-HSA-9664881 (Reactome)
PEX5R-HSA-9664850 (Reactome)
R-HSA-9664850 (Reactome) The first step in pexophagy is the initiation by a signal that triggers downstream events to eventually degrade the peroxisome. Ataxia-telangiectasia mutated protein (ATM) is a serine/threonine protein kinase that is involve in DNA damage response. ATM is known to be involved in pexophagy (Katarzyna ZR et al. 2016). ATM binds with Peroxisomal targeting signal 1 receptor (PEX5) with the help of a SRL binding sequence in ATM (Zhang J et al. 2015).
R-HSA-9664855 (Reactome) Sequestosome 1 (SQSTM1) is an autophagic receptor that recruits ubiquitinated cargo to the autophagosome. SQSTM1 contains a ubiquitin associated (UBA) domain that binds to monoubiquitinated Peroxisomal targeting signal 1 receptor (PEX5) in the peroxisome and an LC3 interacting region (LIR) that binds to Microtubule associated proteins 1A/1B light chain 3B (MAP1LC3B)/LC3 associated with the nascent autophagosome (Pankiv S et al. 2007). Subsequently, the peroxisome is degraded by the autophagy machinery.
R-HSA-9664862 (Reactome) When serine/threonine kinase Ataxia telangiectasia mutated protein (ATM) is activated it can phosphorylate Peroxisomal targeting signal 1 receptor protein (PEX5) at Ser141 (Zhang J et al. 2015).
R-HSA-9664867 (Reactome) Once recruited to the peroxisomal membrane, Next to BRCA1 gene 1 protein (NBR1) can bind with Microtubule associated proteins 1A/1B light chain 3B (MAP1LC3B)/LC3 with the help of its LC3 interacting region (LIR) domain (Kirkin V et al. 2009). This targets the peroxisomes to the autophagosomes and the degradation process starts.
R-HSA-9664871 (Reactome) Pexophagy is known to be regulated by molecular oxygen stress as a means of adaptive response. Low oxygen tension stabilizes Endothelial PAS domain containing protein 1 (EPAS1), which positively regulates the translocation of Next to BRCA1 gene 1 protein (NBR1) from the cytosol to the peroxisomal membrane. NBR1 binds peroxisomes through its JUBA domain (Walter KM et al. 2014).
R-HSA-9664879 (Reactome) After Peroxisomal targeting signal 1 receptor (PEX5) recruits Ataxia telangiectasia mutated protein (ATM) to the peroxisomal membrane, ATM is activated by the reactive oxygen species (ROS). ROS can oxidize and activate ATM by forming a disulphide cross-linked dimer at the Csy2991 residue (Guo Z et al. 2010).
R-HSA-9664880 (Reactome) Autophagic receptors, Next to BRCA1 gene 1 protein (NBR1) and Sequestosome 1 (SQSTM1) cooperate to bind and recruit ubiquitinated peroxisomes to the autophagy machinery. NBR1 and SQSTM1 have similar protein domain architecture and bind to Microtubule associated proteins 1A/1B light chain 3B (MAP1LC3B)/LC3 via an LC3 interacting region (LIR) (Kirkin V et al. 2009). Subsequently, peroxisomes are engulfed within the autophagosome and degraded.
R-HSA-9664881 (Reactome) As autophagy receptors, Next to BRCA1 gene 1 protein (NBR1) and Sequestosome 1 (SQSTM1) can cooperate to achieve pexophagy. SQSTM1 supports NBR1 to bind ubiquitinated peroxisomes through its UBA domain and enhances the efficiency of the degradation process (Kirkin V et al. 2009).
R-HSA-9664883 (Reactome) After the binding of Peroxisomal targeting signal 1 receptor (PEX5) and Ataxia telangiectasia mutated protein (ATM), PEX5 recruits the complex to the peroxisomal membrane for the next steps of the degradation process (Zhang J et al. 2015).
R-HSA-9664888 (Reactome) Phosphorylation of Peroxisomal targeting signal 1 receptor protein (PEX5) at Ser141 promotes the ubiquitination of PEX5. The RING peroxins complex composed of: Peroxisome biogenesis factor 2 (PEX2), Peroxisome biogenesis factor 10 (PEX10), and Peroxisome assembly protein 12 (PEX12) form part of a peroxisome localized E3 ligase that ubiquitinates PEX5 at Lys209 (Zhang J et al. 2015). This mono ubiquitination of PEX5 helps to recruit the autophagy machinery to the peroxisome.
R-HSA-9664892 (Reactome) Sequestosome 1 (SQSTM1) is an autophagy adaptor that serves to bridge ubiquitinated cargo and the autophagosome. It binds ubiquitinated cargo via its UBA domain. SQSTM1 in the cytosol recognizes and binds with ubiquitinated Peroxisomal targeting signal 1 receptor (PEX5) in the peroxisomal membrane (Zhang et al. 2015).
R-HSA-9674127 (Reactome) The deubiquitinase, Ubiquitin carboxyl-terminal hydrolase 30 (USP30) counters the action of E3 ligase on peroxisomal membrane proteins. USP30 can remove ubiquitin moieties from PEX5 thereby preventing pexophagy (Riccio V et al. 2019, Marcassa E et al. 2019)
R-HSA-9674131 (Reactome) As a deubiquitinase, Ubiquitin carboxyl-terminal hydrolase 30 (USP30) can reverse the action of E3 ligase on peroxisomal membrane proteins. Studies show that USP30 can localise in the peroxisomal membrane and interact with ubiquitinated PEX5 (Riccio V et al. 2019, Marcassa E et al. 2019).
ROSArrowR-HSA-9664879 (Reactome)
SQSTM1R-HSA-9664892 (Reactome)
USP30R-HSA-9674131 (Reactome)
UbArrowR-HSA-9674127 (Reactome)
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