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Molecular insights into the hypoxic memory of sickle cell erythrocytes

Abstract : Research on sickle cell erythrocyte physiopathology is essential to improve treatment of sickle cell disease (SCD), a life-threatening haemoglobinopathy caused by genetic mutations of the beta-globin gene. Homozygous SS and heterozygous SC are the most frequent forms of SCD. Our laboratory is working on adenosine signalling, an important regulatory pathway controlling erythrocyte metabolism adjustment and release of O2 to counteract tissue hypoxia. Leading to enhanced Hb deoxygenation, HbS polymerisation and red blood cell sickling, adenosine signalling is thought to be detrimental to SCD. A recent study has revealed that erythrocyte Equilibrative Nucleoside Transporter 1 (eENT1) acts as a key regulatory element of circulating plasma adenosine. This study further reported a reduced eENT1 expression oc-curring as an adaptation to high altitude. The molecular mechanism was shown to involve eENT1 ubiquitination-dependent degradation by the proteasome. In view of these important findings, we sought to determine by Western blot and flow cy-tometry the expression level of ENT1 and total membrane protein ubiquitination of red blood cell samples obtained from HbSS and HbSC patients, and HbAS Sickle cell trait (SCT) subjects. HbAA erythrocytes were used as controls. Results showed a significant 1.5-2 fold-increase of ubiquitinated membrane proteins in erythrocytes of SS and SC patients but no sig-nificant difference in eENT1 expression. Our working hypothesis is that altered activity of the proteasome is responsible for the accumulation of ubiquitinated protein in absence of degra-dation. Interestingly, our study also revealed that SCT erythrocytes display significant 1.5 fold-increase of ubiquitinated membrane proteins and ~0.25-fold reduction of eENT1. SCT is not regarded as a disease but a risk factor, in extreme situations, for a number of complications common to SCD, including sudden death, the most feared complication of SCT. Consequenc-es of altered adenosine signalling on the pathophysiology of SCT erythrocytes deserve further investigation.
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https://hal.univ-antilles.fr/hal-02554092
Contributor : Eliane Falco <>
Submitted on : Friday, April 24, 2020 - 11:31:04 PM
Last modification on : Friday, June 19, 2020 - 11:26:11 AM

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  • HAL Id : hal-02554092, version 1

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L. Reininger, E.T. Ngo Sock, K. Reminy, Sophie Antoine-Jonville, F. Rodriguez-Lima, et al.. Molecular insights into the hypoxic memory of sickle cell erythrocytes. Caribbean Science and Innovation Meeting 2019, Oct 2019, Pointe-à-Pitre (Guadeloupe), France. ⟨hal-02554092⟩

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