title: Betaine homocysteine S-methyltransferase emerges as a new player of the nuclear methionine cycle.
abstract: The paradigm of a cytoplasmic methionine cycle synthesizing/eliminating metabolites that are transported into/out of the nucleus as required has been challenged by detection of significant nuclear levels of several enzymes of this pathway. Here, we show betaine homocysteine S-methyltransferase (BHMT), an enzyme that exerts a dual function in maintenance of methionine levels and osmoregulation, as a new component of the nuclear branch of the cycle. In most tissues, low expression of Bhmt coincides with a preferential nuclear localization of the protein. Conversely, the liver, with very high Bhmt expression levels, presents a main cytoplasmic localization. Nuclear BHMT is an active homotetramer in normal liver, although the total enzyme activity in this fraction is markedly lower than in the cytosol. N-terminal basic residues play a role in cytoplasmic retention and the ratio of glutathione species regulates nucleocytoplasmic distribution. The oxidative stress associated with d-galactosamine (Gal) or buthionine sulfoximine (BSO) treatments induces BHMT nuclear translocation, an effect that is prevented by administration of N-acetylcysteine (NAC) and glutathione ethyl ester (EGSH), respectively. Unexpectedly, the hepatic nuclear accumulation induced by Gal associates with reduced nuclear BHMT activity and a trend towards increased protein homocysteinylation. Overall, our results support the involvement of BHMT in nuclear homocysteine remethylation, although moonlighting roles unrelated to its enzymatic activity in this compartment cannot be excluded.
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain; Departamento de Anatomía y Embriología Humanas, Facultad de Medicina, Universidad Complutense de Madrid, Plaza de Ramón y Cajal s/n, 28040 Madrid, Spain.
authors.forename: Juliana
authors.initials: J
authors.lastname: Pérez-Miguelsanz
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain.
authors.forename: Néstor
authors.initials: N
authors.lastname: Vallecillo
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Garrido
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain.
authors.forename: Edel
authors.initials: E
authors.lastname: Reytor
authors.affiliation: Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: Dolores
authors.initials: D
authors.lastname: Pérez-Sala
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain; Instituto de Investigación Sanitaria La Paz (IdiPAZ), Paseo de la Castellana 261, 28046 Madrid, Spain. Electronic address: mapajares@iib.uam.es.
authors.forename: María A
authors.initials: MA
authors.lastname: Pajares
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D050940:Betaine-Homocysteine S-Methyltransferase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D002467:Cell Nucleus / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D003593:Cytoplasm / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000378:metabolism*; D018384:Oxidative Stress; D021382:Protein Sorting Signals; D051381:Rats; D017208:Rats, Wistar
chemical_list: D021382:Protein Sorting Signals; D008715:Methionine; D050940:Betaine-Homocysteine S-Methyltransferase; C494550:Bhmt protein, rat; D005978:Glutathione
keywords: Betaine homocysteine methyltransferase; Cytosolic retention; Galactosamine intoxication; One-carbon metabolism; Oxidative stress; Subcellular localization