A redox-sensitive transcriptional regulator. Maintains intracellular redox homeostasis by regulating catabolic metabolism and polyketide biosynthesis (PubMed:17609386, PubMed:19680450). Regulates expression of the redox buffer ergothioneine (ERG) in a carbon-source-dependent manner; loss of ERG or mycothiol (MSH, the other major redox buffer in this bacteria) leads to respiratory alterations and bioenergetic deficiencies that negatively impact virulence (PubMed:26774486). In response to low external pH (like that found in host macrophage phagosomes) alters endogenous gene expression leading to acid resistance; MSH and WhiB3 are probably part of a regulatory circuit that mediates gene expression upon acid stress (PubMed:26637353). Regulates pathogenic lipid synthesis, coordinating proprionate flux (and other host-derived fatty acid oxidation intermediates) into methyl-branched fatty acids (polyacyltrehalose, phthiocerol dimycocerosates, sulfolipids) and the storage lipid triacylglycerol, functioning as reductive sink (PubMed:19680450). During intracellular growth M.tuberculosis uses host fatty acids as an energy source, generating large quantities of proprionate and NADH/NADPH, which are toxic and highly reducing respectively. WhiB3 is thought to help dissipate proprionate and NADH/NADPH by switching to the in vivo carbon source and via lipid anabolism (PubMed:19680450). Responds to NO and O(2) (PubMed:17609386). Regulates expression of genes encoding modular polyketide synthases such as pks2, pks3 and fbpA (PubMed:19680450). The oxidized apo-form of WhiB3 binds DNA (with 2 intramolecular disulfide bonds); holo-WhiB3 (with the 4Fe-4S cluster) binds DNA considerably less well (PubMed:19680450). Discriminates poorly between specific and non-specific DNA-binding. Plays a role in virulence and nutritional stress (PubMed:11880648, PubMed:17609386, PubMed:26637353). In its apo-form can act as a protein disulfide reductase (PubMed:18550384). May respond to mycothiol (MSH) redox potential (E-MSH) which decreases at pH 4.5 for up to 72 hours, indicative of cellular reductive stress; deletion of whiB3 leads to a lesser E-MSH at 72 hours, indicative of cellular oxidative stress (PubMed:26637353). Probably via its effects on production of polyketide lipids, regulates host gene expression, leading to blockage of phagosome maturation (PubMed:26637353). Equilibration of extra- and intracytoplasmic pH kills bacteria (PubMed:26637353). Binds 1 [4Fe-4S] cluster per subunit (PubMed:17609386). Following nitrosylation of the [4Fe-4S] cluster binds 1 [4Fe-8(NO)] cluster per subunit (PubMed:17609386). Homodimer (Probable) (PubMed:18550384). Interacts with the C-terminal 54 residues of sigma factor SigA (RpoV) (PubMed:11880648). 100-fold induced in wild-type C57BL/6 mice 2 weeks after lung infection, RNA levels drop to 30X induced 8 weeks post-infection (PubMed:16923787). Similar but less dramatic induction is seen in immunocompromised mice (PubMed:16923787). Rapidly induced in resting mouse macrophages, remains up-regulated for at least 60 hours, continuing induction is repressed by interferon gamma (PubMed:16923787). Induced by growth at acidic pH (PubMed:26637353). The 4Fe-4S cluster interacts with NO, forming a protein-bound dinitrosyliron dithiol complex (PubMed:17609386). The 4Fe-4S cluster interacts with O(2), leading to its degradation. Cluster loss takes about 2 hours (PubMed:17609386). Once in the apo-form the cysteines oxidize to form 2 intramolecular disulfide bonds (PubMed:18550384). Fully reduced protein. Fully oxidized protein. Not essential for growth in culture, or growth in vivo in mouse and guinea pig infections (PubMed:11880648). Disruption significantly enhances survival of immunocompetent mice (PubMed:11880648). Decreased bacterial growth in guinea pig lungs, but not spleen (PubMed:26637353). Growth on minimal media, glucose or succinate is poor, suggesting WhiB3 is involved in starvation response (PubMed:17609386). Growth on acetate is better than wild-type (PubMed:17609386). 55-fold decreased survival at pH 4.5, no difference at pH 5.5 or 6.6 (PubMed:26637353). Altered expression of genes involved in cell wall lipid composition, the ESX-1 secretion system and redox balance, impairs the mycothiol-specific reductive response to acid stress (PubMed:26637353). Dysfunctional respiration when grown in pyruvate, increased intracellular ergothioneine (ERG) production when grown in a number of carbon sources (PubMed:26774486). Upon infection of human THP-1 macrophage-like cells bacteria are localized to acidified lysosomes (M.tuberculosis usually blocks lysosome acidification), do not reduce mycothiol (MSH) and have significantly decreased survival (PubMed:26637353). Leads to up-regulation of host innate immunity genes usually repressed by M.tuberculosis (such as phagosome maturation and TLR signaling) and down-regulation of genes that inhibit autophagy (such as mTOR) (PubMed:26637353). Cell size, shape and surface architecture are perturbed, as is synthesis of cell surface associated virulence lipids both in culture and in cultured macrophages, or in response to oxidizing or reducing agents (PubMed:19680450). Disrupted strains are more resistant to toxic levels of propionate (PubMed:19680450). Belongs to the WhiB family.