Mitochondrial amidoxime-reducing component 1 p.Ala165Thr increases protein degradation mediated by the proteasome.

Autor: Dutta T; Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden., Sasidharan K; Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden., Ciociola E; Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden., Pennisi G; Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.; Section of Gastroenterology and Hepatology, Dipartimento Di Promozione Della Salute, Materno Infantile, Medicina Interna e Specialistica Di Eccellenza (PROMISE), University of Palermo, Palermo, Italy., Noto FR; Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.; Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy., Kovooru L; Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden., Kroon T; Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Lindblom A; Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Du Y; Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom., Pirmoradian M; Translational Science and Experimental Medicine, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Wallin S; Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Mancina RM; Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden., Lindén D; Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.; Division of Endocrinology, Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden., Romeo S; Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.; Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy.; Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
Jazyk: angličtina
Zdroj: Liver international : official journal of the International Association for the Study of the Liver [Liver Int] 2024 May; Vol. 44 (5), pp. 1219-1232. Date of Electronic Publication: 2024 Feb 20.
DOI: 10.1111/liv.15857
Abstrakt: Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health concern with no effective and specific drug treatment available. The rs2642438 minor allele in mitochondrial amidoxime-reducing component 1 (MARC1) results in an aminoacidic substitution (p.Ala165Thr) and associates with protection against MASLD. However, the mechanisms behind this protective effect are unknown. In this study, we examined the consequences of this aminoacidic substitution on protein stability and subcellular localization.
Methods: We overexpressed the human MARC1 A165 (wild-type) or 165T (mutant) in vivo in mice and in vitro in human hepatoma cells (HepG2 and HuH-7), generated several mutants at position 165 by in situ mutagenesis and then examined protein levels. We also generated HepG2 cells stably overexpressing MARC1 A165 or 165T to test the effect of this substitution on MARC1 subcellular localization.
Results: MARC1 165T overexpression resulted in lower protein levels than A165 both in vivo and in vitro. Similarly, any mutant at position 165 showed lower protein levels compared to the wild-type protein. We showed that the 165T mutant protein is polyubiquitinated and its degradation is accelerated through lysine-48 ubiquitin-mediated proteasomal degradation. We also showed that the 165T substitution does not affect the MARC1 subcellular localization.
Conclusions: This study shows that alanine at position 165 in MARC1 is crucial for protein stability, and the threonine substitution at this position leads to a hypomorphic protein variant due to lower protein levels. Our result supports the notion that lowering hepatic MARC1 protein level may be a successful therapeutic strategy for treating MASLD.
(© 2024 The Authors. Liver International published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
Externí odkaz: