DHHC5 facilitates oligodendrocyte development by palmitoylating and activating STAT3

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• The myelin sheath is vital for central nervous system nerve function.
• Protein palmitoylation directs myelin-forming proteins to the myelin membrane.
• The role of palmitoylation in oligodendrocyte development is largely unknown.

Purpose of the Study:

• To investigate the function of DHHC5, a palmitoyl acyltransferase, in oligodendrocyte development and myelination.
• To elucidate the molecular mechanisms by which DHHC5 regulates oligodendrocyte differentiation and myelin formation.

Main Methods:

• Utilized genetic ablation of Zdhhc5 in oligodendrocytes.
• Investigated the impact on myelination and remyelination processes.
• Identified and analyzed STAT3 as a key substrate of DHHC5 palmitoylation.
• Assessed STAT3 phosphorylation, activation, and downstream gene expression.

Main Results:

• Loss of Zdhhc5 in oligodendrocytes significantly inhibited myelination and remyelination.
• DHHC5 deficiency reduced the population of myelinating oligodendrocytes.
• DHHC5 palmitoylates STAT3, and its absence decreased STAT3 palmitoylation, phosphorylation, and activation.
• This led to suppressed transcription of myelin-related and anti-apoptotic genes.

Conclusions:

• DHHC5 plays a critical role in controlling oligodendrocyte development and myelinogenesis.
• DHHC5-mediated STAT3 palmitoylation is essential for regulating myelin gene expression and oligodendrocyte survival.
• These findings highlight DHHC5 as a potential therapeutic target for myelin disorders.