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New K50R mutant mouse models reveal impaired hypusination of eif5a2 with alterations in cell metabolite landscape
Chad R Schultz1, Ryan D Sheldon2, Huirong Xie3
1Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA.
Abstract:
The eukaryotic translation initiation factor 5A1 (eIF5A1) and 5A2 (eIF5A2) are important proteins in a variety of physiological and pathophysiological processes and their function has been linked to neurodevelopmental disorders, cancer, and viral infections. Here, we report two new genome-edited mouse models, generated using a CRISPR-Cas9 approach, in which the amino acid residue lysine 50 is replaced with arginine 50 (K50R) in eIF5A1 or in the closely related eIF5A2 protein. This mutation prevents the spermidine-dependent post-translational formation of hypusine, a unique lysine derivative that is necessary for activation of eIF5A1 and eIF5A2. Mouse brain lysates from homozygous eif5a2-K50R mutant mice (eif5a2K50R/K50R) confirmed the absence of hypusine formation of eIF5A2, and metabolomic analysis of primary mouse dermal fibroblasts revealed significant alterations in the metabolite landscape compared to controls including increased levels of tryptophan, kyrunenine, pyridoxine, nicotinamide adenine dinucleotide, riboflavin, flavin adenine dinucleotide, pantothenate, and coenzyme A. Further supported by new publicly available bioinformatics data, these new mouse models represent excellent in vivo models to study hypusine-dependent biological processes, hypusination-related disorders caused by eIF5A1 and eIF5A2 gene aberrations or mRNA expression dysregulation, as well as several major human cancer types and potential therapies.
Insights
New mouse models with a specific mutation in eukaryotic translation initiation factor 5A1 (eIF5A1) and 5A2 (eIF5A2) prevent hypusine formation. These models aid research into hypusination disorders and cancer therapies.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Eukaryotic translation initiation factor 5A1 (eIF5A1) and 5A2 (eIF5A2) are crucial proteins involved in various physiological and pathophysiological processes.
- Dysregulation of eIF5A1 and eIF5A2 is implicated in neurodevelopmental disorders, cancer, and viral infections.
Purpose of the Study:
- To generate and characterize novel genome-edited mouse models for studying eIF5A1 and eIF5A2 function.
- To investigate the role of hypusination, a critical post-translational modification, in eIF5A protein activity and associated biological processes.
Main Methods:
- CRISPR-Cas9 genome editing was employed to create mouse models with a lysine 50 to arginine 50 (K50R) mutation in eIF5A1 or eIF5A2.
- Confirmation of hypusine absence in eIF5A2 using mouse brain lysates from homozygous eif5a2-K50R mutant mice.
- Metabolomic analysis of primary mouse dermal fibroblasts to identify metabolic alterations.
Main Results:
- The K50R mutation successfully prevented spermidine-dependent hypusine formation in eIF5A1 and eIF5A2.
- Homozygous eif5a2-K50R mutant mice confirmed the absence of eIF5A2 hypusination.
- Metabolomic profiling revealed significant alterations, including increased levels of tryptophan, kyrunenine, and various B vitamins and coenzymes.
Conclusions:
- The generated mouse models are valuable in vivo tools for studying hypusine-dependent biological processes.
- These models can advance research into hypusination-related disorders stemming from eIF5A gene aberrations or mRNA dysregulation.
- The models offer potential for investigating human cancers and therapeutic strategies targeting eIF5A pathways.
