Figure 1.

Simplified hypothetical model for formaldehyde interaction with EBV. a) Alcohol dehydrogenase 3 (ADH3) catalyzes the oxidation of GSH-conjugated formaldehyde (S-hydroxymethylglutathione, HMGSH) to S-formylglutathione (FGSH), and the reduction of GSH-conjugated NO (S-nitrosoglutathione, GSNO) to glutathione sulfinamide (GSONH₂). Both NO and GSNO regulate protein function by S-nitrosylating cysteine residues, albeit with differential specificity. Excessive formaldehyde can accelerate GSNO reduction via NAD⁺/NADH cofactor recycling leading to decreased cellular nitrosothiols. Interleukin-13 has recently been shown to increase ADH3 expression. b) EBV latency programs that contain LMP1 promote latency, in part, through activation of NF-κB pathways. NO appears to be required for latency in programs that lack LMP1, as NOS inhibition can reactivate the EBV in vitro. Similar to LMP1, this process likely involves activation of NF-κB. This NO-mediated regulation of EBV is cGMP-independent and involves S-nitrosylation of RAS by NO and/or GSNO. In addition, binding of the early lytic transcription factor, Zta, to DNA is inhibited by redox and nitrosative modification of cysteine residues. c) Nitrosothiols influence the EBV life cycle. Increased ADH3 expression or excessive formaldehyde exposure from xenobiotic metabolism (e.g. N-nitrosodimethylamine, NDMA) or exogenous sources may accelerate GSNO reduction thereby promoting EBV reactivation. Zta may also increase IL-13, which may in turn increase ADH3 expression. In addition to EBV reactivation, formaldehyde mediated protein modification and DNA reactivity can interact with established EBV latency programs to promote epithelial cell transformation.