title: The AMPKγ1 subunit plays an essential role in erythrocyte membrane elasticity, and its genetic inactivation induces splenomegaly and anemia.
abstract: AMP-activated protein kinase (AMPK) is an αβγ heterotrimer conserved throughout evolution and important for energy sensing in all eukaryote cells. AMPK controls metabolism and various cellular events in response to both hormones and changes in cellular energy status. The γ subunit senses intracellular energy status through the competitive binding of AMP and ATP. We show here that targeted disruption of the mouse AMPKγ1 gene (Prkag1) causes regenerative hemolytic anemia by increasing the sequestration of abnormal erythrocytes. Prkag1(-/-) mice displayed splenomegaly and iron accumulation due to compensatory splenic erythropoiesis and erythrophagocytosis. Moreover, AMPKγ1-deficient erythrocytes were highly resistant to osmotic hemolysis and poorly deformable in response to increasing shear stress, consistent with greater membrane rigidity. No change in cytoskeletal protein composition was observed; however, the phosphorylation level of adducin, a protein promoting the binding of spectrin to actin, was higher in AMPKγ1-deficient erythrocytes. Together, these results demonstrate that AMPKγ1 subunit is required for the maintenance of erythrocyte membrane elasticity.
authors.affiliation: Institut Cochin, Département d'Endocrinologie Métabolisme et Cancer, 24 rue du Faubourg St.-Jacques, 75014 Paris, France. marc.foretz@inserm.fr
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.forename: Sophie
authors.initials: S
authors.lastname: Hébrard
authors.forename: Soizic
authors.initials: S
authors.lastname: Guihard
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Leclerc
authors.forename: Marcio
authors.initials: M
authors.lastname: Do Cruzeiro
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Hamard
authors.forename: Florence
authors.initials: F
authors.lastname: Niedergang
authors.forename: Muriel
authors.initials: M
authors.lastname: Gaudry
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000740:Anemia / Q000097:blood / Q000201:enzymology* / Q000235:genetics; D000743:Anemia, Hemolytic / Q000201:enzymology / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D004548:Elasticity; D004900:Erythroblasts / Q000378:metabolism / Q000473:pathology; D004906:Erythrocyte Count; D004907:Erythrocyte Deformability; D004910:Erythrocyte Membrane / Q000378:metabolism*; D005260:Female; D006965:Hyperplasia; D007501:Iron / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D013163:Splenomegaly / Q000097:blood / Q000201:enzymology* / Q000235:genetics
chemical_list: D008565:Membrane Proteins; C526224:Prkag1 protein, mouse; D007501:Iron; C548179:Prkaa1 protein, mouse; C534978:Prkaa2 protein, mouse; C554549:Prkab1 protein, mouse; D055372:AMP-Activated Protein Kinases