Dynamic modulation of Leishmania cytochrome c oxidase subunit IV (LmCOX4) expression in response to mammalian...

The Leishmania LACK antigen is a ribosome-associated protein that facilitates expression of mitochondrial cytochrome c oxidase subunit IV (LmCOX4) to support parasite mitochondrial fitness and virulence within the vertebrate host. To further examine the relationship between LACK, its putative ribosome binding motif and LmCOX4, we compared the kinetics of LmCOX4 expression following temperature elevation in wildtype LACK (LACK WT) and LACK-putative ribosome-binding mutant (LACK^DDE) L. major. We found that, after initial exposure to mammalian temperature, LmCOX4 levels became undetectable in LACK^DDE L. major and also, surprisingly, in wild type (WT) control strains. Upon sustained exposure to mammalian temperature, LmCOX4 expression returned in WT control strains only. The initial loss of LmCOX4 in WT L. major was substantially reversed by treatment with the proteasome inhibitor MG132. Our findings indicate that initial loss of LmCOX4 under mammalian conditions is dependent upon proteasome degradation and LmCOX4 re-expression is dependent upon LACK possessing a WT putative ribosome binding motif.