Marta Montori-Grau1, Robert Pedreira-Casahuga2, Zoé Boyer-Díaz2, Iréna Lassot3, Celia García-Martínez4, Anna Orozco2, Judith Cebrià5, Oscar Osorio-Conles2, Matilde R Chacón6, Joan Vendrell6, Manuel Vázquez-Carrera7, Solange Desagher3, Josep Carles Jiménez-Chillarón5, Anna Ma Gómez-Foix8. 1. Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona (IBUB), Spain; Institut de Recerca Sant Joan de Déu (IRSJD), Esplugues de Llobregat, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III, Spain; Departament de Farmacologia, Toxicologia i Química Terapéutica, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Spain. Electronic address: mmontori@ub.edu. 2. Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Spain. 3. Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France. 4. Departament de Patologia i Terapèutica Experimental, UB, Hospitalet de Llobregat, Barcelona, Spain. 5. Institut de Recerca Sant Joan de Déu (IRSJD), Esplugues de Llobregat, Barcelona, Spain; Endocrine Division, Esplugues de Llobregat, Barcelona, Spain. 6. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III, Spain; Hospital Universitari de Tarragona Joan XXIII, Universitat Rovira i Virgili, IISPV, Tarragona, Spain. 7. Institut de Biomedicina de la Universitat de Barcelona (IBUB), Spain; Institut de Recerca Sant Joan de Déu (IRSJD), Esplugues de Llobregat, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III, Spain; Departament de Farmacologia, Toxicologia i Química Terapéutica, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Spain. 8. Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona (IBUB), Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III, Spain.
Abstract
BACKGROUND: Glycogenin-interacting protein 1 (GNIP1) is a tripartite motif (TRIM) protein with E3 ubiquitin ligase activity that interacts with glycogenin. These data suggest that GNIP1 could play a major role in the control of glycogen metabolism. However, direct evidence based on functional analysis remains to be obtained. OBJECTIVES: The aim of this study was 1) to define the expression pattern of glycogenin-interacting protein/Tripartite motif containing protein 7 (GNIP/TRIM7) isoforms in humans, 2) to test their ubiquitin E3 ligase activity, and 3) to analyze the functional effects of GNIP1 on muscle glucose/glycogen metabolism both in human cultured cells and in vivo in mice. RESULTS: We show that GNIP1 was the most abundant GNIP/TRIM7 isoform in human skeletal muscle, whereas in cardiac muscle only TRIM7 was expressed. GNIP1 and TRIM7 had autoubiquitination activity in vitro and were localized in the Golgi apparatus and cytosol respectively in LHCN-M2 myoblasts. GNIP1 overexpression increased glucose uptake in LHCN-M2 myotubes. Overexpression of GNIP1 in mouse muscle in vivo increased glycogen content, glycogen synthase (GS) activity and phospho-GSK-3α/β (Ser21/9) and phospho-Akt (Ser473) content, whereas decreased GS phosphorylation in Ser640. These modifications led to decreased blood glucose levels, lactate levels and body weight, without changing whole-body insulin or glucose tolerance in mouse. CONCLUSION: GNIP1 is an ubiquitin ligase with a markedly glycogenic effect in skeletal muscle.
BACKGROUND: Glycogenin-interacting protein 1 (GNIP1) is a tripartite motif (TRIM) protein with E3 ubiquitin ligase activity that interacts with glycogenin. These data suggest that GNIP1 could play a major role in the control of glycogen metabolism. However, direct evidence based on functional analysis remains to be obtained. OBJECTIVES: The aim of this study was 1) to define the expression pattern of glycogenin-interacting protein/Tripartite motif containing protein 7 (GNIP/TRIM7) isoforms in humans, 2) to test their ubiquitin E3 ligase activity, and 3) to analyze the functional effects of GNIP1 on muscle glucose/glycogen metabolism both in human cultured cells and in vivo in mice. RESULTS: We show that GNIP1 was the most abundant GNIP/TRIM7 isoform in human skeletal muscle, whereas in cardiac muscle only TRIM7 was expressed. GNIP1 and TRIM7 had autoubiquitination activity in vitro and were localized in the Golgi apparatus and cytosol respectively in LHCN-M2 myoblasts. GNIP1 overexpression increased glucose uptake in LHCN-M2 myotubes. Overexpression of GNIP1 in mouse muscle in vivo increased glycogen content, glycogen synthase (GS) activity and phospho-GSK-3α/β (Ser21/9) and phospho-Akt (Ser473) content, whereas decreased GS phosphorylation in Ser640. These modifications led to decreased blood glucose levels, lactate levels and body weight, without changing whole-body insulin or glucose tolerance in mouse. CONCLUSION: GNIP1 is an ubiquitin ligase with a markedly glycogenic effect in skeletal muscle.
Authors: Robert C Orchard; Meagan E Sullender; Bria F Dunlap; Dale R Balce; John G Doench; Herbert W Virgin Journal: J Virol Date: 2018-12-10 Impact factor: 5.103
Authors: Wenchun Fan; Katrina B Mar; Levent Sari; Ilona K Gaszek; Qiang Cheng; Bret M Evers; John M Shelton; Mary Wight-Carter; Daniel J Siegwart; Milo M Lin; John W Schoggins Journal: Cell Date: 2021-05-31 Impact factor: 66.850