PEX2:PEX10:PEX12 monoubiquitinates PEX5S,L at cysteine-11

Stable Identifier
R-HSA-8953946
Type
Reaction [transition]
Species
Homo sapiens
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The RING-type E3 ubiquitin ligase sub-complex PEX2:PEX10:PEX12 catalyzes the transfer of ubiquitin from an E2-ubiquitin conjugate (one of Ub:UBE2D1, Ub:UBE2D2, or Ub:UBE2D3) to the cysteine-11 residue of the substrate PEX5L, the peroxisomal matrix protein shuttling receptor (Carvalho et al. 2007; Grou et al. 2008, Okumoto et al. 2011, Sargent et al. 2016, inferred from yeast in Dodt and Gould 1996). The thiol ester bond between ubiquitin and the cysteine residue of PEX5 is unusual among ubiquitin substrates, which usually have isopeptide bonds between ubiquitin and a lysine residue. Monoubiquitination of PEX5 at cysteine-11 is an integral and mandatory step in the PEX5-mediated peroxisomal protein transport pathway; in its absence, PEX5 cannot be extracted from the peroxisomal membrane docking/translocation machinery (the peroxisomal protein translocon), and thus transport of newly synthesized peroxisomal matrix proteins to the organelle matrix stops (Grou et al. 2009). In addition to monoubiquitinating PEX5 during peroxisomal protein import, the PEX2:PEX10:PEX12 complex has also been implicated in pexophagy, a type of selective autophagy targeting peroxisomes. Pexophagy seems to be triggered mainly by ubiquitination of PEX5, which, in this case, can occur either at its cysteine-11 or lysine-209 residues, but ubiquitination of ABCD3 (also known as PMP70) and other peroxisomal membrane proteins may also be involved (Zhang et al. 2015, inferred from mouse in Nordgren et al. 2015, Sargent et al. 2016).

Literature References
PubMed ID Title Journal Year
26086376 Export-deficient monoubiquitinated PEX5 triggers peroxisome removal in SV40 large T antigen-transformed mouse embryonic fibroblasts

Nordgren, M, Francisco, T, Lismont, C, Hennebel, L, Brees, C, Wang, B, Van Veldhoven, PP, Azevedo, JE, Fransen, M

Autophagy 2015
8991089 Multiple PEX genes are required for proper subcellular distribution and stability of Pex5p, the PTS1 receptor: evidence that PTS1 protein import is mediated by a cycling receptor

Dodt, G, Gould, SJ

J. Cell Biol. 1996
18359941 Members of the E2D (UbcH5) family mediate the ubiquitination of the conserved cysteine of Pex5p, the peroxisomal import receptor

Grou, CP, Carvalho, AF, Pinto, MP, Wiese, S, Piechura, H, Meyer, HE, Warscheid, B, Sá-Miranda, C, Azevedo, JE

J. Biol. Chem. 2008
24662292 Distinct modes of ubiquitination of peroxisome-targeting signal type 1 (PTS1) receptor Pex5p regulate PTS1 protein import

Okumoto, K, Noda, H, Fujiki, Y

J. Biol. Chem. 2014
27597759 PEX2 is the E3 ubiquitin ligase required for pexophagy during starvation

Sargent, G, van Zutphen, T, Shatseva, T, Zhang, L, Di Giovanni, V, Bandsma, R, Kim, PK

J. Cell Biol. 2016
26344566 ATM functions at the peroxisome to induce pexophagy in response to ROS

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

Nat. Cell Biol. 2015
19208625 Properties of the ubiquitin-pex5p thiol ester conjugate

Grou, CP, Carvalho, AF, Pinto, MP, Huybrechts, SJ, Sá-Miranda, C, Fransen, M, Azevedo, JE

J. Biol. Chem. 2009
21554508 Cysteine ubiquitination of PTS1 receptor Pex5p regulates Pex5p recycling

Okumoto, K, Misono, S, Miyata, N, Matsumoto, Y, Mukai, S, Fujiki, Y

Traffic 2011
17726030 Ubiquitination of mammalian Pex5p, the peroxisomal import receptor

Carvalho, AF, Pinto, MP, Grou, CP, Alencastre, IS, Fransen, M, Sá-Miranda, C, Azevedo, JE

J. Biol. Chem. 2007
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Title
ubiquitin protein ligase activity of PEX2:PEX10:PEX12:PEX5S,L:Ub:UBE2D1,2,3:PEX13:PEX14 [peroxisomal membrane]
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