Combinatorial selective ER-phagy remodels the ER during neurogenesis

Area of Science:

• Cell Biology
• Neuroscience
• Molecular Biology

Background:

• The endoplasmic reticulum (ER) is vital for cellular functions, including protein synthesis and calcium homeostasis.
• Neuronal development requires precise ER remodeling, with defects linked to neurological disorders.
• Selective autophagy, particularly ER-phagy, is implicated in ER quality control, but its mechanisms and receptor roles remain unclear.

Approach:

• Utilized a genetically tractable induced neuron (iNeuron) system for in vitro monitoring of ER remodeling during differentiation.
• Integrated proteomic and computational tools to create a quantitative map of ER proteome remodeling via selective autophagy.
• Analyzed single and combinatorial ER-phagy receptor mutants to assess their contributions to ER protein clearance.

Key Points:

• Defined specific subsets of ER membrane and lumenal proteins as preferred targets for distinct ER-phagy receptors.
• Demonstrated receptor-specific autophagic capture of ER in neuronal axons using spatial sensors and flux reporters.
• Visualized tubular ER membranes within autophagosomes in neuronal projections via cryo-electron tomography.

Conclusions:

• Established a quantitative framework for understanding how individual ER-phagy receptors reshape the ER during cellular transitions.
• Provided insights into the molecular mechanisms of selective ER removal and its importance in neuronal structure and function.
• Developed a versatile genetic toolkit for further investigation of ER remodeling and autophagy in neuroscience.