MsrB1 (methionine-R-sulfoxide reductase 1) knock-out mice: Roles of MsrB1 in redox regulation and identification of a novel selenoprotein form

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

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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.

Original languageEnglish
Pages (from-to)5986-5993
Number of pages8
JournalJournal of Biological Chemistry
Volume284
Issue number9
DOIs
Publication statusPublished - 2009 Feb 27
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Fomenko, D. E., Novoselov, S. V., Natarajan, S. K., Lee, B. C., Koc, A., Carlson, B. A., Lee, T. H., Kim, H. Y., Hatfield, D. L., & Gladyshev, V. N. (2009). MsrB1 (methionine-R-sulfoxide reductase 1) knock-out mice: Roles of MsrB1 in redox regulation and identification of a novel selenoprotein form. Journal of Biological Chemistry, 284(9), 5986-5993. https://doi.org/10.1074/jbc.M805770200