The SET29 and SET7 proteins of Leishmania donovani exercise non-redundant convergent as well as collaborative functions in moderating the parasite's response to oxidative stress.

SET proteins are lysine methyltransferases. In investigating Leishmania donovani SET29, we found depletion of LdSET29 by two-thirds did not affect promastigote growth, nor alter the parasite's response to UV-induced or HU-induced stress, but made it more tolerant to HO-induced oxidizing environment. The deviant response to oxidative stress was coupled to lowered accumulation of reactive oxygen species, which was linked to enhanced scavenging activity. The set29 mutants' response to HO exposure was similar to that of set7 mutants, prompting an investigation into genetic and physical interactions between the two proteins. While neither protein could rescue the aberrant phenotypes of the other set mutant, the two proteins interacted physically in vitro and in vivo. Transcriptome analyses revealed that neither protein regulated global gene expression, but LdSET7 controlled transcript levels of a limited number of genes, including several peroxidases. In working towards identifying targets through which SET7/SET29 mediate the cell's response to an oxidative milieu, we found HSP60/CNP60 and TCP1 to be possible candidates. LdHSP60 has earlier been implicated in the regulation of the response of virulent promastigotes to HO exposure, and LdTCP1 has previously been found to have a protective effect against oxidative stress. set7 and set29 mutants survived more proficiently in host macrophages as well. The data suggest an alliance between LdSET29 and LdSET7 in mounting the parasite's response to oxidative stress, each protein playing its own distinctive role. They ensure the parasite not only establishes infection, but also maintains the balance with host cells to enable the persistence of infection.