MsrB1 (methionine-R-sulfoxide reductase 1) knock-out mice

Roles of MsrB1 in redox regulation and identification of a novel selenoprotein form

Dmitri Fomenko, Sergey V. Novoselov, Sathish K Natarajan, Byung Cheon Lee, Ahmet Koc, Bradley A. Carlson, Tae Hyung Lee, Hwa Young Kim, Dolph L. Hatfield, Vadim N. Gladyshev

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

Protein oxidation has been linked to accelerated aging and is a contributing factor to many diseases. Methionine residues are particularly susceptible to oxidation, but the resulting mixture of methionine R-sulfoxide (Met-RO) and methionine S-sulfoxide (Met-SO) can be repaired by thioredoxin-dependent enzymes MsrB and MsrA, respectively. Here, we describe a knock-out mouse deficient in selenoprotein MsrB1, the main mammalian MsrB located in the cytosol and nucleus. In these mice, in addition to the deletion of 14-kDa MsrB1, a 5-kDa selenoprotein form was specifically removed. Further studies revealed that the 5-kDa protein occurred in both mouse tissues and human HEK 293 cells; was down-regulated by MsrB1 small interfering RNA, selenium deficiency, and selenocysteine tRNA mutations; and was immunoprecipitated and recognized by MsrB1 antibodies. Specific labeling with 75Se and mass spectrometry analyses revealed that the 5-kDa selenoprotein corresponded to the C-terminal sequence of MsrB1. The MsrB1 knock-out mice lacked both 5- and 14-kDa MsrB1 forms and showed reduced MsrB activity, with the strongest effect seen in liver and kidney. In addition, MsrA activity was decreased by MsrB1 deficiency. Liver and kidney of the MsrB1 knock-out mice also showed increased levels of malondialdehyde, protein carbonyls, protein methionine sulfoxide, and oxidized glutathione as well as reduced levels of free and protein thiols, whereas these parameters were little changed in other organs examined. Overall, this study established an important contribution of MsrB1 to the redox control in mouse liver and kidney and identified a novel form of this protein.

Original languageEnglish (US)
Pages (from-to)5986-5993
Number of pages8
JournalJournal of Biological Chemistry
Volume284
Issue number9
DOIs
StatePublished - Feb 27 2009

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Methionine Sulfoxide Reductases
Selenoproteins
Knockout Mice
Oxidation-Reduction
Liver
Proteins
sulfoxide
Kidney
Methionine
Oxidation
Thioredoxins
Glutathione Disulfide
HEK293 Cells
Selenium
Malondialdehyde
Sulfhydryl Compounds
Cytosol
Labeling
Small Interfering RNA
Mass spectrometry

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

MsrB1 (methionine-R-sulfoxide reductase 1) knock-out mice : Roles of MsrB1 in redox regulation and identification of a novel selenoprotein form. / Fomenko, Dmitri; Novoselov, Sergey V.; Natarajan, Sathish K; Lee, Byung Cheon; Koc, Ahmet; Carlson, Bradley A.; Lee, Tae Hyung; Kim, Hwa Young; Hatfield, Dolph L.; Gladyshev, Vadim N.

In: Journal of Biological Chemistry, Vol. 284, No. 9, 27.02.2009, p. 5986-5993.

Research output: Contribution to journalArticle

Fomenko, Dmitri ; Novoselov, Sergey V. ; Natarajan, Sathish K ; Lee, Byung Cheon ; Koc, Ahmet ; Carlson, Bradley A. ; Lee, Tae Hyung ; Kim, Hwa Young ; Hatfield, Dolph L. ; Gladyshev, Vadim N. / MsrB1 (methionine-R-sulfoxide reductase 1) knock-out mice : Roles of MsrB1 in redox regulation and identification of a novel selenoprotein form. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 9. pp. 5986-5993.
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abstract = "Protein oxidation has been linked to accelerated aging and is a contributing factor to many diseases. Methionine residues are particularly susceptible to oxidation, but the resulting mixture of methionine R-sulfoxide (Met-RO) and methionine S-sulfoxide (Met-SO) can be repaired by thioredoxin-dependent enzymes MsrB and MsrA, respectively. Here, we describe a knock-out mouse deficient in selenoprotein MsrB1, the main mammalian MsrB located in the cytosol and nucleus. In these mice, in addition to the deletion of 14-kDa MsrB1, a 5-kDa selenoprotein form was specifically removed. Further studies revealed that the 5-kDa protein occurred in both mouse tissues and human HEK 293 cells; was down-regulated by MsrB1 small interfering RNA, selenium deficiency, and selenocysteine tRNA mutations; and was immunoprecipitated and recognized by MsrB1 antibodies. Specific labeling with 75Se and mass spectrometry analyses revealed that the 5-kDa selenoprotein corresponded to the C-terminal sequence of MsrB1. The MsrB1 knock-out mice lacked both 5- and 14-kDa MsrB1 forms and showed reduced MsrB activity, with the strongest effect seen in liver and kidney. In addition, MsrA activity was decreased by MsrB1 deficiency. Liver and kidney of the MsrB1 knock-out mice also showed increased levels of malondialdehyde, protein carbonyls, protein methionine sulfoxide, and oxidized glutathione as well as reduced levels of free and protein thiols, whereas these parameters were little changed in other organs examined. Overall, this study established an important contribution of MsrB1 to the redox control in mouse liver and kidney and identified a novel form of this protein.",
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AU - Novoselov, Sergey V.

AU - Natarajan, Sathish K

AU - Lee, Byung Cheon

AU - Koc, Ahmet

AU - Carlson, Bradley A.

AU - Lee, Tae Hyung

AU - Kim, Hwa Young

AU - Hatfield, Dolph L.

AU - Gladyshev, Vadim N.

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N2 - Protein oxidation has been linked to accelerated aging and is a contributing factor to many diseases. Methionine residues are particularly susceptible to oxidation, but the resulting mixture of methionine R-sulfoxide (Met-RO) and methionine S-sulfoxide (Met-SO) can be repaired by thioredoxin-dependent enzymes MsrB and MsrA, respectively. Here, we describe a knock-out mouse deficient in selenoprotein MsrB1, the main mammalian MsrB located in the cytosol and nucleus. In these mice, in addition to the deletion of 14-kDa MsrB1, a 5-kDa selenoprotein form was specifically removed. Further studies revealed that the 5-kDa protein occurred in both mouse tissues and human HEK 293 cells; was down-regulated by MsrB1 small interfering RNA, selenium deficiency, and selenocysteine tRNA mutations; and was immunoprecipitated and recognized by MsrB1 antibodies. Specific labeling with 75Se and mass spectrometry analyses revealed that the 5-kDa selenoprotein corresponded to the C-terminal sequence of MsrB1. The MsrB1 knock-out mice lacked both 5- and 14-kDa MsrB1 forms and showed reduced MsrB activity, with the strongest effect seen in liver and kidney. In addition, MsrA activity was decreased by MsrB1 deficiency. Liver and kidney of the MsrB1 knock-out mice also showed increased levels of malondialdehyde, protein carbonyls, protein methionine sulfoxide, and oxidized glutathione as well as reduced levels of free and protein thiols, whereas these parameters were little changed in other organs examined. Overall, this study established an important contribution of MsrB1 to the redox control in mouse liver and kidney and identified a novel form of this protein.

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