Arsenite-inducible RNA-associated protein (AIRAP) protects cells from arsenite toxicity

Abstract

Exposure of cells to arsenicals activates multiple stress pathways resulting in the induction of specific genes whose identity and role in the adaptation to arsenical-induced cellular stress are poorly understood. We report here the identification of a novel gene encoding an arsenite-inducible, cysteine- and histidine-rich RNA-associated protein, AIRAP, that is conserved among mammals, Drosophila and C elegans. Immunochemistry and cell fractionation experiments indicate that, when induced, AIRAP is present in both the nucleus and the cytoplasm, and cross-linking experiments indicate that it associates with RNA in vivo. The expression of a C elegans homologue of AIRAP, aip-1, is also induced by exposure to arsenite, and expression of an aip-1::gfp transgene is most pronounced in hypodermal cells. RNA-mediated interference (RNAi) of aip-1 lowers the resistance of nematodes to arsenite yet does not appear to affect viability under standard growth conditions. These experiments suggest a role for AIRAP/AIP-1 in protecting cells from the toxic effects of arsenite.

Proteasomal adaptation to environmental stress links resistance to proteotoxicity with longevity in Caenorhabditis elegans

“…The hsp-16 pr::gfp strain has been described previously (11), and the daf- 16 RNAi Feeding, Arsenite Treatment, and Lifespan Studies. RNAi feeding protocols, bacteria containing aip-1, daf-16, and hsf-1 RNAi vectors, and procedures used to expose worms to arsenite were described previously (12,27). The 250 bp after the stop codon of aip-1 was amplified by PCR to construct an RNAi feeding vector targeting aip-1's mRNA 3Ј-UTR.…”

“…Inactivation of aip-1 by RNAi sensitizes worms to the acute toxic effects of exposure to sodium arsenite (11,12). However, under normal growth conditions, aip-1(RNAi) worms developed normally, were morphologically indistinguishable from reference animals, and produced a normal number of progeny (Fig.…”

“…A second mammalian gene predicted to encode a constitutively expressed AIRAP homologue, AIRAPL, also exists and is characterized here. Worms have measurable basal levels of aip-1 mRNA (12), suggesting that a single gene incorporates features of both the arsenic-inducible AIRAP and the constitutively expressed AIRAPL. Here, we report that AIP-1 plays an important role in preserving the lifespan of worms and in buffering proteotoxicity in circumstances that are not associated with exposure to arsenic.…”

Reprofiled drug targets ancient protozoans

“…AIRAP is unique among known arseniteinduced genes because its expression is not upregulated in response to other oxidants and is only modestly induced by exposure to other metals, such as zinc. 39 The upregulation of the transcript for a gene similar to that encoding AIRAP is not surprising since both arsenite and auranofin are inhibitors of thioredoxin reductase. [40][41][42][43] Auranofin had half-maximal inhibitory concentration (IC 50 ) of 0.4 μM against active, recombinant E. histolytica thioredoxin reductase (EhTrxR).…”

Functional Genomic Assessment of Phosgene-Induced Acute Lung Injury in Mice

“…In addition to ZFAND4, mouse lung ZFAND2A and ZFAND5 transcripts increased more in the SM/J than in the 129X1/SvJ ( Figure 8C). Previous investigations have found that ZFAND2A expression is induced by arsenite (114,115) and heat shock (116). Similarly in macrophages, ZFAND5 expression is induced by cell stress in response to TNF, IFNg, LPS, and other toll-like receptor ligands (117)(118)(119).…”