ERYTHROPOIESIS AND AUTOPHAGY: TWO CLOSELY RELATED PARTNERS.

FADER CM

Paraná - Entre Rios

Congreso; 54th Annual Meeting Argentine Society for Biochemistry and Molecular Biology; 2018

SAIB

Erythroid maturation is a highly regulated process where immature cells from bone marrow go through a series of differentiation stages to become mature red blood cells. During this, essential intracellular modifications take place such as degradation of entire organelles that are non-necessary for erythrocyte functionality. Autophagy is a lysosomal degradative pathway where macromolecules and organelles are surrounded by double membrane vesicles called autophagosomes and then targeted to lysosomes for its degradation. Autophagy participates actively in erythropoiesis being responsible for engulfment and elimination of mitochondria (mitophagy) and ribosomes once all hemoglobin has been synthesized. Low density lipoprotein receptor-related protein 1 (LRP1) is a transmembrane receptor involved in a wide range of cellular processes such as proliferation, differentiation and metabolism. LRP1 participates as a scavenger receptor for hemin-hemopexin complex, leading to its endocytic internalization for metabolism. We have demonstrated that hemin, an erythropoiesis inductor, is able to generate an autophagic response (mitophagy) in erythroleukemia cells lines (K562 cells), inducing the expression of LRP1 and some autophagic genes such as LC3, Atg5 and Beclin1. Importantly, we have demonstrated that hemin target LRP1 to autophagosomes and this receptor is in part responsible for hemin autophagy activation. Moreover, hemin induces a traffic modification of LRP1, increasing its localization in later endosomal compartments including lysosomal vesicles. It has been proposed that autophagy manipulation is a feasible new therapeutic key in erythropoietic disorders as well as in fighting cancer. Taken together, our results suggest that hemin via LRP1 receptor, is favoring erythroid maturation by inducing an autophagic response in K562 cells, being a possible therapeutic candidate that helps in hematopoietic disorders as well as the chronic myelogenous leukemia (CML) treatment.