title: CUL4A-DDB1-Rbx1 E3 ligase controls the quality of the PTS2 receptor Pex7p.
abstract: 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.
authors.affiliation: *Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Miyauchi-Nanri
authors.affiliation: *Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Mukai
authors.affiliation: †Graduate School of Systems Life Sciences, Kyushu University, Fukuoka 812-8581, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kuroda
authors.forename: Yukio
authors.initials: Y
authors.lastname: Fujiki
mesh_terms: D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018902:Chondrodysplasia Punctata, Rhizomelic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006224:Cricetinae; D003412:Cricetulus; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D000074437:Peroxisomal Targeting Signal 2 Receptor / Q000172:deficiency; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*
chemical_list: C114234:CUL4A protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; C091435:DDB1 protein, human; D004268:DNA-Binding Proteins; C000614269:PEX7 protein, human; D000074437:Peroxisomal Targeting Signal 2 Receptor; C479529:RBX1 protein, human; D018160:Receptors, Cytoplasmic and Nuclear