Mutation of serine 32 to threonine in peroxiredoxin 6 preserves enzymatic activity but prevents trafficking to lamellar bodies in vivo (950.1)

Abstract

Peroxiredoxin 6 (Prdx6), a peroxidase that also expresses phospholipase A2 (aiPLA2) activity, protects lungs from oxidative stress and participates in lung surfactant phospholipid (PL) turnover. Prdx6 has been localized to both cytosolic and acidic (lamellar body [LB] and lysosomal) compartments in lung epithelium. We propose that Prdx6 LB targeting facilitates its role in the degradation and remodeling of lung surfactant phosphatidylcholine. Although, we have previously shown that mutation of serine 32 (S32) to alanine abolishes Prdx6 aiPLA2 activity, we now show that serine to threonine mutation has no effect on either Prdx6 peroxidase or aiPLA2 activity. Since S32 is a necessary component of the amino acid motif that mediates Prdx6 LB targeting, we studied the effect of the S32T mutation on Prdx6 LB localization. In a “knock‐in” mouse model carrying an S32T mutation in the Prdx6 gene, there was phospholipid (PL) accumulation in the lung and a marked decrease in aiPLA2 activity in LB. Prdx6 was absent from LB of mutant mice by both western blot and immunofluorescence analysis despite normal protein expression in lung epithelial cells. Thus, the S32T mutation preserves the PLA2 activity of Prdx6 but does not support its targeting to LB, which results in PL accumulation, despite the normal Prdx6 PLA2 activity in lung tissue.Grant Funding Source: HL102016 and HL105509