Unc 51-like autophagy-activating kinase (ULK1) mediates clearance of free α-globin in β-thalassemia

BioRxiv : the Preprint Server for Biology
Christophe M LechauveMitchell J. Weiss

Abstract

Erythroid maturation is coordinated to maximize the production of hemoglobin A heterotetramers (a2b2) and minimize the accumulation of potentially toxic free alpha or beta globin subunits. In beta thalassemia, mutations in the B globin gene cause a buildup of free alpha globin, which forms intracellular precipitates that impair erythroid cell maturation and viability. Protein quality-control systems mitigate beta thalassemia pathophysiology by degrading toxic free alpha globin. We show that loss of the Unc 51 like autophagy activating kinase gene Ulk1 in beta thalassemic mice reduces autophagic clearance of a globin in red cell precursors and exacerbates disease phenotypes, whereas inactivation of the canonical autophagy gene Atg5 has minimal effects. Systemic treatment with rapamycin to inhibit the ULK1 inhibitor mTORC1 reduces alpha globin precipitates and lessens pathologies in beta thalassemic mice, but not in those lacking Ulk1. Similarly, rapamycin reduces free α-globin accumulation in erythroblasts derived from B thalassemic patient CD34+ hematopoietic progenitors. Our findings identify a new, drug regulatable pathway for ameliorating beta thalassemia.

Related Concepts

Autophagy
Beta-Globins
Beta Thalassemia
Cell Survival
Erythroblasts
Erythrocytes
Globin
Hemoglobin
Laboratory mice
Pathologic Processes

Related Feeds

Autophagosome

An autophagosome is the formation of double-membrane vesicles that involve numerous proteins and cytoplasmic components. These double-membrane vesicles are then terminated at the lysosome where they are degraded. Discover the latest research on autophagosomes here.

Autophagy & Model Organisms

Autophagy is a cellular process that allows degradation by the lysosome of cytoplasmic components such as proteins or organelles. Here is the latest research on autophagy & model organisms

BioRxiv & MedRxiv Preprints

BioRxiv and MedRxiv are the preprint servers for biology and health sciences respectively, operated by Cold Spring Harbor Laboratory. Here are the latest preprint articles (which are not peer-reviewed) from BioRxiv and MedRxiv.

Anemia

Anemia develops when your blood lacks enough healthy red blood cells. Anemia of inflammation (AI, also called anemia of chronic disease) is a common, typically normocytic, normochromic anemia that is caused by an underlying inflammatory disease. Here is the latest research on anemia.

Autophagosome

An autophagosome is the formation of double-membrane vesicles that involve numerous proteins and cytoplasmic components. These double-membrane vesicles are then terminated at the lysosome where they are degraded. Discover the latest research on autophagosomes here.