engleski

INTERPLAY BETWEEN C TERMINAL BNIP3L/NIX PHOSPHORYLATION AND DIMERIZATION AS A NOVEL MECHANISM OF RECEPTORMEDIATED MITOPHAGY REGULATION

Autophagy is an essential and a conventional regulation mechanism in all eukaryotic cells, conserved throughout the evolution and indispensable for optimal function of each cell. To maintain homeostasis, autophagy balances the biosynthesis and catabolism of different macromolecules to protect against diverse pathologies, including cancer or neurodegeneration. As the most important energetic organelles, mitochondria play a pivotal role in intracellular homeostasis, thus the maintenance of mitochondrial function and integrity is crucial for normal physiology. A form of autophagy specialized for selective removal of mitochondria, mitophagy, is needed for elimination of dysfunctional mitochondria whose accumulation can lead to the development of various diseases. Conversely, programmed mitophagy of healthy mitochondria is prerequisite for differentiation of particular cell types and autophagy receptor BNIP3L/NIX is shown to be a key for mitochondrial removal during erythropoiesis. We have uncovered completely novel mechanism of selectivity underlying BNIP3L/NIXmediated mitophagy. This mechanism involves the interplay between C terminal BNIP3L/NIX dephosphorylation and consequently receptor dimerization. Stable BNIP3L/NIX homodimers provide the formation of strong interactions between the receptor and autophagosomal proteins, more robust recruitment of autophagosomes and more efficient mitochondrial removal. Analysis of C terminal intermembrane part of BNIP3L/NIX has revealed that receptor dimerization is achieved by specific Ser212 dephosphorylation and has the same effect on mitophagy process as LIR phosphorylation described earlier. We have observed the interplay between BNIP3L/NIX phosphorylation and dimerization, together with LIR phosphorylation, is needed for proper BNIP3L/NIX-dependent mitophagy initiation and progression. Currently, the focus of our research is in detailed analysis of interactions between BNIP3L/NIX and identified kinases/phosphatases to unveil upstream signaling pathways that trigger and regulate mitophagy especially in erythroid cell lines. This knowledge is crucial for better understanding the mechanisms of particular cell`s differentiation and the development of pathological conditions that underlie the disturbed mitophagy process.

BNIP3L/NIX ; mitophagy ; dimerization ; autophagy

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