Transcriptomic Changes Predict Metabolic Alterations in LC3 Associated Phagocytosis in Aged Mice

Area of Science:

• Cell Biology
• Molecular Biology
• Ophthalmology

Background:

• LC3b (Map1lc3b) is crucial for canonical autophagy and non-canonical functions like LC3-associated phagocytosis (LAP).
• LAP is vital for phagosome maturation and degradation in specialized cells, including retinal pigment epithelial (RPE) cells.
• Dysfunctional LAP contributes to retinal lipid steatosis, metabolic dysregulation, and inflammation.

Purpose of the Study:

• To investigate the transcriptomic changes in RPE cells lacking LC3b.
• To determine how the loss of LAP-mediated processes affects genes involved in metabolic homeostasis, lipid handling, and inflammation.
• To identify molecular pathways and gene families altered by LC3b deficiency in the RPE.

Main Methods:

• Comparative transcriptome analysis of RPE cells from wild-type (WT) and LC3b-deficient (LC3b-/-) mice.
• Identification of differentially expressed genes (DEGs) using RNA sequencing.
• Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) to identify enriched biological processes and pathways.

Main Results:

• 1533 differentially expressed genes (DEGs) were identified in LC3b-/- RPE cells, with 73% upregulated and 27% downregulated.
• Enriched GO terms included inflammatory response (upregulated) and fatty acid metabolism/vascular transport (downregulated).
• GSEA revealed 28 upregulated pathways (inflammation-related) and 6 downregulated pathways (metabolic). Significant alterations were observed in solute carrier family genes, RPE signature genes, and genes linked to age-related macular degeneration.

Conclusions:

• Loss of LC3b significantly alters the RPE transcriptome, promoting lipid dysregulation and metabolic imbalance.
• LC3b deficiency contributes to RPE atrophy, inflammation, and disease pathophysiology.
• Understanding these transcriptomic changes provides insights into the role of LAP in retinal health and disease.