title: Nitration of Hsp90 induces cell death.
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.
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA.
authors.forename: Maria Clara
authors.initials: MC
authors.lastname: Franco
authors.forename: Yaozu
authors.initials: Y
authors.lastname: Ye
authors.forename: Christian A
authors.initials: CA
authors.lastname: Refakis
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Feldman
authors.forename: Audrey L
authors.initials: AL
authors.lastname: Stokes
authors.forename: Manuela
authors.initials: M
authors.lastname: Basso
authors.forename: Raquel M
authors.initials: RM
authors.lastname: Melero Fernández de Mera
authors.forename: Nicklaus A
authors.initials: NA
authors.lastname: Sparrow
authors.forename: Noel Y
authors.initials: NY
authors.lastname: Calingasan
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Kiaei
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Rhoads
authors.forename: Thong C
authors.initials: TC
authors.lastname: Ma
authors.forename: Martin
authors.initials: M
authors.lastname: Grumet
authors.forename: Stephen
authors.initials: S
authors.lastname: Barnes
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Beckman
authors.forename: Ryan
authors.initials: R
authors.lastname: Mehl
authors.forename: Alvaro G
authors.initials: AG
authors.lastname: Estévez
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000502:physiology*; D004195:Disease Models, Animal; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D030421:Peroxynitrous Acid / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D051381:Rats; D013119:Spinal Cord Injuries / Q000378:metabolism / Q000473:pathology; D014443:Tyrosine / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: C491901:FAS protein, human; D018841:HSP90 Heat-Shock Proteins; D019014:fas Receptor; D030421:Peroxynitrous Acid; D014443:Tyrosine