Pex7p is the cytosolic receptor for peroxisomal matrix proteins harbouring PTS2 (peroxisome-targeting signal type-2). Mutations in the PEX7 gene cause RCDP (rhizomelic chondrodysplasia punctata) type 1, a distinct PTS2-import-defective phenotype of peroxisome biogenesis disorders. The mechanisms by which the protein level and quality of Pex7p are controlled remain largely unknown. In the present study we show that dysfunctional Pex7p, including mutants from RCDP patients, is degraded by a ubiquitin-dependent proteasomal pathway involving the CRL4A (Cullin4A-RING ubiquitin ligase) complex. Furthermore, we demonstrate that the degradation of dysfunctional Pex7p is essential for maintaining normal PTS2 import, thereby suggesting that CRL4A functions as an E3 ligase in the quality control of Pex7p. Our results define a mechanism underlying Pex7p homoeostasis and highlight its importance for regulating PTS2 import. These findings may lead to a new approach to Pex7p-based therapies for the treatment of peroxisome biogenesis disorders such as RCDP.
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Research Article|
September 08 2014
CUL4A-DDB1-Rbx1 E3 ligase controls the quality of the PTS2 receptor Pex7p
Yasuhiro Miyauchi-Nanri;
Yasuhiro Miyauchi-Nanri
*Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan
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Satoru Mukai;
Satoru Mukai
*Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan
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Kosuke Kuroda;
Kosuke Kuroda
†Graduate School of Systems Life Sciences, Kyushu University, Fukuoka 812-8581, Japan
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Yukio Fujiki
Yukio Fujiki
1
*Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan
†Graduate School of Systems Life Sciences, Kyushu University, Fukuoka 812-8581, Japan
1To whom correspondence should be addressed (email yfujiki@kyudai.jp).
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Publisher: Portland Press Ltd
Received:
July 02 2013
Revision Received:
May 19 2014
Accepted:
July 03 2014
Accepted Manuscript online:
July 03 2014
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem J (2014) 463 (1): 65–74.
Article history
Received:
July 02 2013
Revision Received:
May 19 2014
Accepted:
July 03 2014
Accepted Manuscript online:
July 03 2014
Citation
Yasuhiro Miyauchi-Nanri, Satoru Mukai, Kosuke Kuroda, Yukio Fujiki; CUL4A-DDB1-Rbx1 E3 ligase controls the quality of the PTS2 receptor Pex7p. Biochem J 1 October 2014; 463 (1): 65–74. doi: https://doi.org/10.1042/BJ20130861
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