MGST1, a GSH transferase/peroxidase essential for development and hematopoietic stem cell differentiation
Lars Bräutigam,
Jie Zhang,
Kristian Dreij,
Linda Spahiu,
Arne Holmgren,
Hiroshi Abe,
Kenneth D. Tew,
Danyelle M. Townsend,
Michael J. Kelner,
Ralf Morgenstern,
Katarina Johansson
Affiliations
Lars Bräutigam
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
Jie Zhang
Departments of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, United States
Kristian Dreij
Institute of Environmental Medicine, Division of Biochemical Toxicology, Karolinska Institutet, SE 17177 Stockholm, Sweden
Linda Spahiu
Institute of Environmental Medicine, Division of Biochemical Toxicology, Karolinska Institutet, SE 17177 Stockholm, Sweden
Arne Holmgren
Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden
Hiroshi Abe
Department of Chemistry, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-Ku, Nagoya 464-8602, Japan
Kenneth D. Tew
Departments of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, United States
Danyelle M. Townsend
Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, United States
Michael J. Kelner
Department of Pathology, University of California, San Diego, MC7721, La Jolla, CA 92093-7721, United States
Ralf Morgenstern
Institute of Environmental Medicine, Division of Biochemical Toxicology, Karolinska Institutet, SE 17177 Stockholm, Sweden; Corresponding author.
Katarina Johansson
Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden
We show for the first time that, in contrast to other glutathione transferases and peroxidases, deletion of microsomal glutathione transferase 1 (MGST1) in mice is embryonic lethal. To elucidate why, we used zebrafish development as a model system and found that knockdown of MGST1 produced impaired hematopoiesis. We show that MGST1 is expressed early during zebrafish development and plays an important role in hematopoiesis. High expression of MGST1 was detected in regions of active hematopoiesis and co-expressed with markers for hematopoietic stem cells. Further, morpholino-mediated knock-down of MGST1 led to a significant reduction of differentiated hematopoietic cells both from the myeloid and the lymphoid lineages. In fact, hemoglobin was virtually absent in the knock-down fish as revealed by diaminofluorene staining. The impact of MGST1 on hematopoiesis was also shown in hematopoietic stem/progenitor cells (HSPC) isolated from mice, where it was expressed at high levels. Upon promoting HSPC differentiation, lentiviral shRNA MGST1 knockdown significantly reduced differentiated, dedicated cells of the hematopoietic system. Further, MGST1 knockdown resulted in a significant lowering of mitochondrial metabolism and an induction of glycolytic enzymes, energetic states closely coupled to HSPC dynamics. Thus, the non-selenium, glutathione dependent redox regulatory enzyme MGST1 is crucial for embryonic development and for hematopoiesis in vertebrates. Keywords: Embryonic development, Hematopoiesis, Redox regulation, Microsomal glutathione transferase/peroxidase
