NDLI: Nitrosative-stress induced S-glutathionylation of PDI leads to activation of the unfolded protein response

Content Provider	PubMed Central
Author	Townsend, Danyelle M. Manevich, Yefim He, Lin Xiong, Ying Bowers, Robert R. Hutchens, Steven Tew, Kenneth D.
Abstract	The rapid proliferation of cancer cells mandates a high protein turnover. The endoplasmic reticulum (ER) is intimately involved in protein processing. An accumulation of unfolded or misfolded proteins in the ER leads to a cascade of transcriptional and translational events collectively referred to as the unfolded protein response (UPR). Protein disulfide isomerase (PDI) is one of the most abundant ER proteins and maintains a sentinel function in organizing accurate protein folding. Treatment of cells with PABA/NO (O 2- [2,4-dinitro-5- (N-methyl-N-4-carboxyphenylamino) phenyl] 1-N, N-dimethylamino) diazen-1-ium-1, 2-diolate) resulted in a dose dependent increase in intracellular NO that caused S-glutathionylation of various proteins. Within 4h, PABA/NO activated the UPR and led to translational attenuation as measured by the phosphorylation and activation of the ER transmembrane kinase, PERK, and its downstream effector eIF2 in human leukemia (HL60) and ovarian cancer cells (SKOV3). Cleavage of the transcription factor, XBP-1 and transcriptional activation of the ER resident proteins, BiP, PDI, GRP94 and ERO1 (5-10 fold induction) also occurred. Immunoprecipitation of PDI showed that while nitrosylation was undetectable, PABA/NO treatment caused S-glutathionylation of PDI. Mass spectroscopy analysis showed that single cysteine residues within each of the catalytic sites of PDI had a mass increase [+305.3 Da] consistent with S-glutathionylation. Circular dichroism confirmed that S-glutathionylation of PDI results in alterations in the alpha-helix content of PDI and is concurrent with inhibition of its isomerase activity. Thus, it appears that S-glutathionylation of PDI is an upstream signaling event in the UPR and may be linked with the cytotoxic potential of PABA/NO.
Related Links	http://dx.doi.org/10.1158/0008-5472.can-09-0493
Ending Page	7634
Page Count	9
Starting Page	7626
File Format	PDF
ISSN	00085472
e-ISSN	15387445
Journal	Cancer research
Issue Number	19
Volume Number	69
Language	English
Publisher Date	2009-10-01
Access Restriction	Open
Subject Keyword	Cancer Research Oncology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology

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