Reactome | PEX2:PEX10:PEX12 monoubiquitinates PEX5L at cysteine-11

PEX2:PEX10:PEX12 monoubiquitinates PEX5L at cysteine-11

Stable Identifier

R-HSA-9033485

Type

Reaction [transition]

Species

Homo sapiens

Compartment

peroxisomal membrane

ReviewStatus

5/5

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PEX2:PEX10:PEX12 monoubiquitinates PEX5L at cysteine-11

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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). In contrast to PEX5, PEX7 transiently associated with the docking and translocation module (which comprises PEX14, PEX13, PEX2, PEX10, and PEX12) is not ubiquitinated. 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 and PEX7 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 sub-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
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 Gould, SJ, Dodt, G	J. Cell Biol.	1996
26086376	Export-deficient monoubiquitinated PEX5 triggers peroxisome removal in SV40 large T antigen-transformed mouse embryonic fibroblasts Nordgren, M, Lismont, C, Hennebel, L, Wang, B, Brees, C, Azevedo, JE, Van Veldhoven, PP, Fransen, M, Francisco, T	Autophagy	2015
18359941	Members of the E2D (UbcH5) family mediate the ubiquitination of the conserved cysteine of Pex5p, the peroxisomal import receptor Wiese, S, Sá-Miranda, C, Piechura, H, Grou, CP, Meyer, HE, Carvalho, AF, Warscheid, B, Azevedo, JE, Pinto, MP	J. Biol. Chem.	2008
27597759	PEX2 is the E3 ubiquitin ligase required for pexophagy during starvation Di Giovanni, V, Zhang, L, Sargent, G, van Zutphen, T, Kim, PK, Shatseva, T, Bandsma, R	J. Cell Biol.	2016
26344566	ATM functions at the peroxisome to induce pexophagy in response to ROS Kim, J, Walker, CL, Pandita, TK, Charaka, VK, Jing, J, Dere, R, Zhang, J, Kastan, MB, Lee, JH, Alexander, A, Pandita, RK, Paull, TT, Tripathi, DN, Powell, RT, Tait-Mulder, J	Nat. Cell Biol.	2015
19208625	Properties of the ubiquitin-pex5p thiol ester conjugate Huybrechts, SJ, Sá-Miranda, C, Grou, CP, Carvalho, AF, Azevedo, JE, Pinto, MP, Fransen, M	J. Biol. Chem.	2009
21554508	Cysteine ubiquitination of PTS1 receptor Pex5p regulates Pex5p recycling Miyata, N, Mukai, S, Okumoto, K, Misono, S, Matsumoto, Y, Fujiki, Y	Traffic	2011
24865970	A PEX7-centered perspective on the peroxisomal targeting signal type 2-mediated protein import pathway Rodrigues, TA, Grou, CP, Brites, P, Alencastre, IS, Azevedo, JE, Fransen, M, Francisco, T	Mol. Cell. Biol.	2014