Affiliation:
1. Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, 3755 Cote-Ste-Catherine Road, Montreal, Quebec H3T 1E2, Canada
2. Department of Medicine, McGill University, Montreal, Quebec H3A 2T5, Canada
Abstract
ABSTRACT
In iron-replete cells the posttranscriptional regulator IRP2 undergoes ubiquitination and proteasomal degradation. A similar response occurs in cells exposed to sodium nitroprusside (SNP), an NO-releasing drug. It has been proposed that nitroprusside ([Fe(CN)
5
NO]
2−
) fails to donate iron into cells and that it promotes IRP2 degradation via S nitrosylation at C178. This residue is located within a stretch of 73 amino acids, earlier proposed to define an iron-dependent degradation domain. Surprisingly, we show that IRP2 bearing a C178S mutation or a Δ73 deletion is sensitive to degradation not only by ferric ammonium citrate (FAC) but also by SNP. Moreover, FAC and SNP attenuate the RNA-binding activities of IRP2 and its homologue IRP1 with similar kinetics. Actinomycin D, cycloheximide, succinylacetone, and dimethyl-oxalylglycine antagonize IRP2 degradation in response to both FAC and SNP, suggesting a common mechanistic basis. IRP2 is not only sensitive to fresh, but also to photodegraded SNP and remains unaffected by
S
-nitrosoglutathione (GSNO), an established nitrosation agent. Importantly, both fresh and photodegraded SNP, but not GSNO, promote a >4-fold increase in the calcein-accessible labile iron pool. Collectively, these results suggest that IRP2 degradation by SNP does not require S nitrosylation but rather represents a response to iron loading.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
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