FICD activity and AMPylation remodelling modulate human neurogenesis

Area of Science:

• Molecular Biology
• Neuroscience
• Biochemistry

Background:

• Posttranslational modification (PTM) is crucial for cellular functions.
• AMPylation (adenylylation) is an emerging PTM regulating protein activity.
• FICD protein is the primary studied AMPylating enzyme in human cells.

Purpose of the Study:

• Investigate the role of AMPylation in human neurogenesis.
• Utilize a novel probe to study AMPylation pathways in various human cell types.
• Identify AMP-modified proteins and their functions in neural development.

Main Methods:

• Employed a cell-permeable propargyl adenosine pronucleotide probe.
• Analyzed AMPylation in cancer cell lines, stem cells, neural progenitor cells (NPCs), neurons, and cerebral organoids (COs).
• Utilized Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS) and imaging techniques.

Main Results:

• Identified a total of 162 AMP-modified proteins.
• Demonstrated that FICD-dependent AMPylation remodelling accelerates NPC differentiation in COs.
• Revealed a previously unknown trigger for human neurogenesis.

Conclusions:

• AMPylation plays a significant role in human neurogenesis.
• FICD-mediated AMPylation is a key regulator of neural differentiation.
• This study uncovers a novel mechanism controlling the development of mature neurons.