Title

Nitration of Hsp90 induces cell death

Authors

Authors

M. C. Franco; Y. Z. Ye; C. A. Refakis; J. L. Feldman; A. L. Stokes; M. Basso; Rmmf de Mera; N. A. Sparrow; N. Y. Calingasan; M. Kiaei; T. W. Rhoads; T. C. Ma; M. Grumet; S. Barnes; M. F. Beal; J. S. Beckman; R. Mehl;A. G. Estevez

Comments

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Abbreviated Journal Title

Proc. Natl. Acad. Sci. U. S. A.

Keywords

apoptosis; peroxynitrite; PC12 cells; AMYOTROPHIC-LATERAL-SCLEROSIS; SPINAL-CORD-INJURY; PEROXYNITRITE-INDUCED; APOPTOSIS; PROTEIN-TYROSINE NITRATION; MOTOR-NEURON APOPTOSIS; NITRIC-OXIDE; PC12 CELLS; SUPEROXIDE-DISMUTASE; INCREASED; 3-NITROTYROSINE; CHAPERONE MACHINERY; Multidisciplinary Sciences

Abstract

Oxidative stress is a widely recognized cause of cell death associated with neurodegeneration, inflammation, and aging. Tyrosine nitration in these conditions has been reported extensively, but whether tyrosine nitration is a marker or plays a role in the cell-death processes was unknown. Here, we show that nitration of a single tyrosine residue on a small proportion of 90-kDa heat-shock protein (Hsp90), is sufficient to induce motor neuron death by the P2X7 receptor-dependent activation of the Fas pathway. Nitrotyrosine at position 33 or 56 stimulates a toxic gain of function that turns Hsp90 into a toxic protein. Using an antibody that recognizes the nitrated Hsp90, we found immunoreactivity in motor neurons of patients with amyotrophic lateral sclerosis, in an animal model of amyotrophic lateral sclerosis, and after experimental spinal cord injury. Our findings reveal that cell death can be triggered by nitration of a single protein and highlight nitrated Hsp90 as a potential target for the development of effective therapies for a large number of pathologies.

Journal Title

Proceedings of the National Academy of Sciences of the United States of America

Volume

110

Issue/Number

12

Publication Date

1-1-2013

Document Type

Article

Language

English

First Page

E1102

Last Page

E1111

WOS Identifier

WOS:000317521600006

ISSN

0027-8424

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