title: The EBAX-type Cullin-RING E3 ligase and Hsp90 guard the protein quality of the SAX-3/Robo receptor in developing neurons.
abstract: Although protein quality control (PQC) is generally perceived as important for the development of the nervous system, the specific mechanisms of neuronal PQC have remained poorly understood. Here, we report that C. elegans Elongin BC-binding axon regulator (EBAX-1), a conserved BC-box protein, regulates axon guidance through PQC of the SAX-3/Robo receptor. EBAX-1 buffers guidance errors against temperature variations. As a substrate-recognition subunit in the Elongin BC-containing Cullin-RING ubiquitin ligase (CRL), EBAX-1 also binds to DAF-21, a cytosolic Hsp90 chaperone. The EBAX-type CRL and DAF-21 collaboratively regulate SAX-3-mediated axon pathfinding. Biochemical and imaging assays indicate that EBAX-1 specifically recognizes misfolded SAX-3 and promotes its degradation in vitro and in vivo. Importantly, vertebrate EBAX also shows substrate preference toward aberrant Robo3 implicated in horizontal gaze palsy with progressive scoliosis (HGPPS). Together, our findings demonstrate a triage PQC mechanism mediated by the EBAX-type CRL and DAF-21/Hsp90 that maintains the accuracy of neuronal wiring.
authors.affiliation: Neurobiology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Wang
authors.forename: Yanli
authors.initials: Y
authors.lastname: Hou
authors.forename: Xing
authors.initials: X
authors.lastname: Guo
authors.forename: Monique
authors.initials: M
authors.lastname: van der Voet
authors.forename: Mike
authors.initials: M
authors.lastname: Boxem
authors.forename: Jack E
authors.initials: JE
authors.lastname: Dixon
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Chisholm
authors.forename: Yishi
authors.initials: Y
authors.lastname: Jin
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000502:physiology*; D044842:Cullin Proteins / Q000502:physiology*; D004330:Drosophila; D000075065:Elongin; D018841:HSP90 Heat-Shock Proteins; D051379:Mice; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000378:metabolism*; D009420:Nervous System / Q000196:embryology* / Q000378:metabolism; D055495:Neurogenesis; D009474:Neurons; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D000097905:Roundabout Proteins
chemical_list: D029742:Caenorhabditis elegans Proteins; D044842:Cullin Proteins; D000075065:Elongin; D018841:HSP90 Heat-Shock Proteins; D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D044767:Ubiquitin-Protein Ligases; D000097905:Roundabout Proteins; C510188:DAF-21 protein, C elegans; C584248:EBAX-1 protein, C elegans