Endoplasmic reticulum stress increases the expression of methylenetetrahydrofolate reductase through the IRE1 transducer.
Methylenetetrahydrofolate reductase (MTHFR), an enzyme in folate and homocysteine metabolism, influences many cellular processes including methionine and nucleotide synthesis, methylation reactions, and maintenance of homocysteine at nontoxic levels. Mild deficiency of MTHFR is common in many populations and modifies risk for several complex traits including vascular disease, birth defects, and cancer. We recently demonstrated that MTHFR can be up-regulated by NF-kappaB, an important mediator of cell survival that is activated by endoplasmic reticulum (ER) stress. This observation, coupled with the reports that homocysteine can induce ER stress, prompted us to examine the possible regulation of MTHFR by ER stress. We found that several well characterized stress inducers (tunicamycin, thapsigargin, and A23187) as well as homocysteine could increase Mthfr mRNA and protein in Neuro-2a cells. The induction of MTHFR was also observed after overexpression of inositol-requiring enzyme-1 (IRE1) and was inhibited by a dominant-negative mutant of IRE1. Because IRE1 triggers c-Jun signaling, we examined the possible involvement of c-Jun in up-regulation of MTHFR. Transfection of c-Jun and two activators of c-Jun (LiCl and sodium valproate) increased MTHFR expression, whereas a reported inhibitor of c-Jun (SP600125) and a dominant-negative derivative of c-Jun N-terminal kinase-1 reduced MTHFR activation. We conclude that ER stress increases MTHFR expression and that IRE1 and c-Jun mediate this activation. These findings provide a novel mechanism by which the ER can regulate homeostasis and allude to an important role for MTHFR in cell survival.
Departments of Human Genetics and Pediatrics, McGill University Health Center-Montreal Children's Hospital, Montreal H3Z 2Z3, Canada.
Daniel
D
Leclerc
Departments of Human Genetics and Pediatrics, McGill University Health Center-Montreal Children's Hospital, Montreal H3Z 2Z3, Canada. Electronic address: rima.rozen@mcgill.ca.
Rima
R
Rozen
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004722:Endoribonucleases / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D006710:Homocysteine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); C403982:ERN2 protein, human; D017346:Protein Serine-Threonine Kinases; D048055:Mitogen-Activated Protein Kinase 8; D004722:Endoribonucleases