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Evaluation of LC3-II Release via Extracellular Vesicles in Relation to the Accumulation of Intracellular LC3-positive Vesicles
Published on: October 18, 2024
The evolutionarily conserved PRP4K-CHMP4B/vps32 splicing circuit regulates autophagy
Sabateeshan Mathavarajah1, Sandhya Chipurupalli1, Elias B Habib1
1Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada.
Abstract:
The pre-mRNA processing factor 4 kinase (PRP4K) is an essential gene in animal cells, making interrogation of its function challenging. Here, we report characterization of a viable knockout model of PRP4K in the social amoeba Dictyostelium discoideum, revealing a function for PRP4K in splicing events controlling autophagy. When prp4k knockout amoebae undergo multicellular development, we observe defects in differentiation linked to abnormal autophagy and aberrant secretion of stalk cell inducer c-di-GMP. Autophagosome-lysosome fusion is impaired after PRP4K loss in both human cell lines and amoebae. PRP4K loss results in mis-splicing and reduced expression of the ESCRT-III gene CHMP4B in human cells and its ortholog vps32 in Dictyostelium, and re-expression of CHMP4B or Vps32 cDNA (respectively) restores normal autophagosome-lysosome fusion in PRP4K-deficient cells. Thus, our work reveals a PRP4K-CHMP4B/vps32 splicing circuit regulating autophagy that is conserved over at least 600 million years of evolution.
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