LACK , a RACK 1 ortholog, facilitates cytochrome c oxidase subunit expression to promote L eishmania major fitness

Summary L eishmania are kinetoplastid parasites that cause the sandfly‐transmitted disease leishmaniasis. To maintain fitness throughout their infectious life cycle, L eishmania must undergo rapid metabolic adaptations to the dramatically distinct environments encountered during transition between sandfly and vertebrate hosts. We performed proteomic and immunoblot analyses of attenuated L . major strains deficient for LACK , the L eishmania ortholog of the mammalian receptor for activated c kinase ( RACK 1), that is important for parasite thermotolerance and virulence . This approach identified cytochrome c oxidase ( LmCOX ) subunit IV as a LACK ‐dependent fitness protein. Consistent with decreased levels of LmCOX subunit IV at mammalian temperature, and in amastigotes, LmCOX activity and mitochondrial function were also impaired in LACK ‐deficient L . major under these conditions. Importantly, overexpression of LmCOX subunit IV in LACK ‐deficient L . major restored thermotolerance and macrophage infectivity. Interestingly, overexpression of LmCOX subunit IV enhanced LmCOX subunit VI expression at mammalian temperature. Collectively, our data suggest LACK promotes L eishmania adaptation to the mammalian host environment by sustaining LmCOX subunit IV expression and hence energy metabolism in response to stress stimuli such as heat. These findings extend the repertoire of RACK 1 protein utility to include a role in mitochondrial function.