A redox-sensitive peroxiredoxin that is important for longevity has tissue- and stress-specific roles in stress resistance

doi:10.1073/pnas.0805507105

A redox-sensitive peroxiredoxin that is important for longevity has tissue- and stress-specific roles in stress resistance

^aInstitute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom;
^bJoslin Diabetes Center, Boston, MA 02215; and
^cNagoya University, Chikusa-ku, Nagoya 464-8602, Japan

Edited by Kathryn V. Anderson, Sloan–Kettering Institute, New York, NY, and approved October 16, 2008 (received for review June 10, 2008)

Abstract

Oxidative damage caused by reactive oxygen species (ROS) is implicated in many diseases and in aging. Removal of ROS by antioxidant enzymes plays an important part in limiting this damage. For instance, peroxiredoxins (Prx) are conserved, abundant, thioredoxin peroxidase enzymes that function as tumor suppressors. In addition to detoxifying peroxides, studies in single-cell systems have revealed that Prx act as chaperones and redox sensors. However, it is unknown in what manner the different activities of Prx influence stress resistance or longevity in the context of whole animals. Here, we reveal three distinct roles for the 2-Cys Prx, PRDX-2, in the stress resistance of the nematode worm Caenorhabditis elegans. (i) The thioredoxin peroxidase activity of PRDX-2 protects against hydrogen peroxide. (ii) Consistent with a chaperone activity for hyperoxidized PRDX-2, peroxide-induced oxidation of PRDX-2 increases resistance to heat stress. (iii) Unexpectedly, loss of PRDX-2 increases the resistance of C. elegans to some oxidative stress-causing agents, such as arsenite, apparently through a signaling mechanism that increases the levels of other antioxidants and phase II detoxification enzymes. Despite their increased resistance to some forms of oxidative stress, prdx-2 mutants are short-lived. Moreover, intestinal expression of PRDX-2 accounts for its role in detoxification of exogenous peroxide, but not its influence on either arsenite resistance or longevity, suggesting that PRDX-2 may promote longevity and protect against environmental stress through different mechanisms. Together the data reveal that in metazoans Prx act through multiple biochemical activities, and have tissue-specific functions in stress resistance and longevity.

Footnotes

¹To whom correspondence may be addressed. E-mail: keith.blackwell{at}joslin.harvard.edu or e.a.veal{at}ncl.ac.uk
Author contributions: M.O. and E.A.V. designed research; M.O. and E.A.V. performed research; M.O., S.R.T., S.K., J.W., K.M., and T.K.B. contributed new reagents/analytic tools; M.O. and E.A.V. analyzed data; and M.O., B.A.M., T.K.B., and E.A.V. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0805507105/DCSupplemental.