Transcriptomic changes predict metabolic alterations in LC3 associated phagocytosis in aged mice

Area of Science:

• Cell Biology
• Molecular Biology
• Ophthalmology

Background:

• Microtubule-associated protein 1A/1B-light chain 3 beta (LC3b) is crucial for autophagy and LC3-associated phagocytosis (LAP).
• LAP is vital for phagosome maturation and degradation in specialized cells like retinal pigment epithelial (RPE) cells.
• Dysfunctional LAP and LC3b deficiency are linked to retinal lipid steatosis, metabolic dysregulation, and inflammation.

Approach:

• Investigated the RPE transcriptome in wild-type (WT) and LC3b-deficient (LC3b-/-) mice using a non-biased approach.
• Analyzed differential gene expression (DEGs), enriched gene ontology (GO) terms, and gene set enrichment analysis (GSEA) pathways.
• Examined specific gene families including solute carriers and RPE signature genes.

Key Points:

• Loss of LC3b resulted in 1533 differentially expressed genes (DEGs) in RPE cells, with 73% upregulated and 27% downregulated.
• Upregulated DEGs were enriched for inflammatory response pathways, while downregulated DEGs were associated with fatty acid metabolism and vascular transport.
• GSEA revealed 28 upregulated pathways (primarily inflammation-related) and 6 downregulated pathways (primarily metabolic).

Conclusions:

• LC3b deficiency significantly alters RPE gene expression, impacting metabolic homeostasis and lipid handling.
• The absence of LC3b-mediated LAP contributes to RPE atrophy, inflammation, and the pathophysiology of retinal diseases.
• These findings highlight LC3b's critical role in maintaining RPE function and preventing retinal lipid dysregulation.