SIR2

TgSIR2 is annotated as a sirtuin-family (HDAC-type) protein in Toxoplasma gondii whose only characterized activity in the available corpus is an immunomodulatory effect on host macrophages. When supplied exogenously as recombinant protein (rTgSIR2), it altered proliferation, apoptosis, and phagocytosis of murine Ana-1 macrophages and modulated secretion of nitric oxide and pro- and anti-inflammatory cytokines in vitro, in the RH strain context (PMID:33731306). Beyond this single in vitro observation, the protein's intrinsic deacetylase mechanism, in-parasite substrates, and pathway placement have not been characterized in the available corpus.

1. 2021 Low

   Whether TgSIR2 has any role beyond a presumed intracellular deacetylase was unknown; treating host macrophages with the recombinant protein established that it can modulate host immune-cell behavior.

   Evidence In vitro treatment of murine Ana-1 macrophages with recombinant TgSIR2 protein, assessing proliferation, apoptosis, phagocytosis, and cytokine/NO secretion

   PMID:33731306

   Open questions at the time

   • Single lab, single set of in vitro assays with recombinant protein; not independently confirmed
   • No enzymatic (deacetylase) activity demonstrated and no substrate identified
   • No in-parasite loss-of-function or mutagenesis to establish endogenous function or pathway placement

• The intrinsic enzymatic mechanism of TgSIR2 and its authentic in-parasite substrates and localization remain undefined.
• No demonstration of NAD-dependent deacetylase activity
• No identified histone or non-histone substrates within the parasite
• No genetic requirement or subcellular localization established