4.7 Article

Gbb glutathionylation promotes its proteasome-mediated degradation to inhibit synapse growth

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JOURNAL OF CELL BIOLOGY
卷 222, 期 9, 页码 -

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ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.202202068

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Glutathionylation is a vital posttranslational modification involved in nervous system development, regulating synapse growth through the degradation of Gbb. This study uncovers the crosstalk between glutathionylation and ubiquitination, providing new insights into their interplay.
Glutathionylation is a posttranslational modification involved in various molecular and cellular processes. However, it remains unknown whether and how glutathionylation regulates nervous system development. To identify critical regulators of synapse growth and development, we performed an RNAi screen and found that postsynaptic knockdown of glutathione transferase omega 1 (GstO1) caused significantly more synaptic boutons at the Drosophila neuromuscular junctions. Genetic and biochemical analysis revealed an increased level of glass boat bottom (Gbb), the Drosophila homolog of mammalian bone morphogenetic protein (BMP), in GstO1 mutants. Further experiments showed that GstO1 is a critical regulator of Gbb glutathionylation at cysteines 354 and 420, which promoted its degradation via the proteasome pathway. Moreover, the E3 ligase Ctrip negatively regulated the Gbb protein level by preferentially binding to glutathionylated Gbb. These results unveil a novel regulatory mechanism in which glutathionylation of Gbb facilitates its ubiquitin-mediated degradation. Taken together, our findings shed new light on the crosstalk between glutathionylation and ubiquitination of Gbb in synapse development. GstO1 postsynaptically suppresses the growth of the Drosophila neuromuscular junctions by inhibiting the BMP signaling pathway. GstO1 interacts with Gbb and prompts its glutathionylation. E3 ligase Ctrip binds glutathionylated Gbb and facilitates its proteasome-mediated degradation, indicating a crosstalk between glutathionylation and ubiquitination in regulating Gbb homeostasis.

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