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Drosophila Rae1 controls the abundance of the ubiquitin ligase Highwire in post-mitotic neurons.

ABSTRACT: The evolutionarily conserved Highwire (Hiw)/Drosophila Fsn E3 ubiquitin ligase complex is required for normal synaptic morphology during development and axonal regeneration after injury. However, little is known about the molecular mechanisms that regulate the Hiw E3 ligase complex. Using tandem affinity purification techniques, we identified Drosophila Rae1 as a previously unknown component of the Hiw/Fsn complex. Loss of Rae1 function in neurons results in morphological defects at the neuromuscular junction that are similar to those seen in hiw mutants. We found that Rae1 physically and genetically interacts with Hiw and restrains synaptic terminal growth by regulating the MAP kinase kinase kinase Wallenda. Moreover, we found that the Rae1 is both necessary and sufficient to promote Hiw protein abundance, and it does so by binding to Hiw and protecting Hiw from autophagy-mediated degradation. These results describe a previously unknown mechanism that selectively controls Hiw protein abundance during synaptic development.

SUBMITTER: Tian X

PROVIDER: S-EPMC3183334 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Drosophila Rae1 controls the abundance of the ubiquitin ligase Highwire in post-mitotic neurons.

Tian Xiaolin X Li Jing J Valakh Vera V DiAntonio Aaron A Wu Chunlai C

Nature neuroscience 20110828 10

The evolutionarily conserved Highwire (Hiw)/Drosophila Fsn E3 ubiquitin ligase complex is required for normal synaptic morphology during development and axonal regeneration after injury. However, little is known about the molecular mechanisms that regulate the Hiw E3 ligase complex. Using tandem affinity purification techniques, we identified Drosophila Rae1 as a previously unknown component of the Hiw/Fsn complex. Loss of Rae1 function in neurons results in morphological defects at the neuromus ...[more]

PMID: 21874015

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Project description:A comprehensive understanding of the molecular machinery important for nociception is essential to improving the treatment of pain. Here, we show that the BMP signaling pathway regulates nociception downstream of the E3 ubiquitin ligase highwire (hiw). hiw loss of function in nociceptors caused antagonistic and pleiotropic phenotypes with simultaneous insensitivity to noxious heat but sensitized responses to optogenetic activation of nociceptors. Thus, hiw functions to both positively and negatively regulate nociceptors. We find that a sensory reception-independent sensitization pathway was associated with BMP signaling. BMP signaling in nociceptors was up-regulated in hiw mutants, and nociceptor-specific expression of hiw rescued all nociception phenotypes including the increased BMP signaling. Blocking the transcriptional output of the BMP pathway with dominant negative Mad suppressed nociceptive hypersensitivity that was induced by interfering with hiw. The up-regulated BMP signaling phenotype in hiw genetic mutants could not be suppressed by mutation in wallenda suggesting that hiw regulates BMP in nociceptors via a wallenda independent pathway. In a newly established Ca2+ imaging preparation, we observed that up-regulated BMP signaling caused a significantly enhanced Ca2+ signal in the axon terminals of nociceptors that were stimulated by noxious heat. This response likely accounts for the nociceptive hypersensitivity induced by elevated BMP signaling in nociceptors. Finally, we showed that 24-hour activation of BMP signaling in nociceptors was sufficient to sensitize nociceptive responses to optogenetically-triggered nociceptor activation without altering nociceptor morphology. Overall, this study demonstrates the previously unrevealed roles of the Hiw-BMP pathway in the regulation of nociception and provides the first direct evidence that up-regulated BMP signaling physiologically sensitizes responses of nociceptors and nociception behaviors.

Dataset Information

Drosophila Rae1 controls the abundance of the ubiquitin ligase Highwire in post-mitotic neurons.

Publications

Drosophila Rae1 controls the abundance of the ubiquitin ligase Highwire in post-mitotic neurons.

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