Various post-translational modifications (PTMs), including glutathionylation, phosphorylation, ubiquitination, methylation and acetylation, affect various aspects of development, physiology and pathogenesis. S-glutathionylation is a specific PTM of protein cysteine residues involving the reversible addition of the tripeptide glutathione (GSH), the most abundant and important low-molecular-mass thiol. Glutathionylated proteins appear uniformly distributed in the cerebral and cerebellar cortex of human brain. However, how glutathionylation regulates neural development remains unclear.
Synapses are specialized connections between neurons and their target cells, so they are critical to brain function. ZHANG Yongqing's laboratory has studied molecular and cellular mechanisms to regulate synaptic development and function using Drosophila neuromuscular junction as a model for a long time. To identify critical regulators of synapse growth and development, They 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 experiment 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 Gbb protein level by preferentially binding to glutathionylated Gbb.
These results unveiled for the first time a novel regulatory mechanism in which glutathionylation of Gbb facilitates its ubiquitin-mediated degradation. Taken together, their findings shed new light on the crosstalk between glutathionylation and ubiquitination of Gbb in synapse development. Glutathionylation may act as a sensor of redox state, nitric oxide, or reactive oxygen species during cellular processes. Their results shew that GstO1 expression was reduced while Gbb increased under hypoxia and in hyperexcitable mutants.
This study was published in Journal of Cell Biology (DOI: 10.1083/jcb.202202068) entitled “Gbb glutathionylation promotes its proteasome-mediated degradation to inhibit synapse growth”. This study was jointly carried out in the laboratories of Professor CHEN Chang in the Institute of Biophysics, Associate Professor YAO Aiyu and Professor ZHANG Yongqing in the Institute of Genetics and Developmental Biology, Chinese Academy of Sciences.
This work was supported in part by the Ministry of Science and Technology of China, the National Natural Science Foundation of China, the Chinese Academy of Sciences Strategic Priority Research Program B grants, and Spring City Plan: the High-level Talent Promotion and Training Project of Kunming.
A working model. GstO1 promotes glutathionylation and subsequent proteasome-mediated degradation of Gbb, while Grx1 does the opposite. GstO1 and Ctrip negatively regulate NMJ synapse development by down-regulating Gbb protein level. (Image by IGDB)
Contact:
Dr. YAO Aiyu and Dr. ZHANG Yongqing
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences
CAS
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A working model. GstO1 promotes glutathionylation and subsequent proteasome-mediated degradation of Gbb, while Grx1 does the opposite. GstO1 and Ctrip negatively regulate NMJ synapse development by down-regulating Gbb protein level. (Image by IGDB)Contact:Dr. YAO Aiyu and Dr. ZHANG YongqingInstitute of Genetics and Developmental Biology, Chinese Academy of Sciences