Regulation of central metabolism genes of Mycobacterium tuberculosis by parallel feed-forward loops controlled by...

Cells respond to external stimuli through networks of regulatory interactions. The human pathogen Mycobacterium tuberculosis responds to stress encountered during infection by arresting multiplication and implementing critical metabolic changes that lead to or sustain the nonreplicative state. Much of this differentiation program is recapitulated when M. tuberculosis cultures are subjected to gradual oxygen depletion in vitro. Here we report that hypoxic induction of critical central metabolism genes in the glyoxylate shunt (icl1) and in the methylcitrate cycle (gltA1) involves both global and local regulators. The global regulators are accessory sigma factors σ(B) for icl1 and σ(E) for gltA1. The local regulators are the products of two paralogous genes mapping at positions adjacent to the corresponding effector gene or operon. We call these genes lrpI and lrpG (for local regulatory protein of icl1 and gltA1). We also found that (i) each sigma factor controls the corresponding local regulator, (ii) both global and local regulators are required for effector gene induction, and (iii) the occurrence of sigma factor control of effector gene induction is independent of its control over the corresponding local regulator. Together, these data indicate that induction of icl1 and gltA1 utilizes parallel feed-forward loops with an AND input function. Both feed-forward loops are affected by σ(E), since this sigma factor is part of the gltA1 loop and controls sigB in the icl1 loop. Feed-forward loops may critically contribute to the cellular developmental program associated with M. tuberculosis dormancy.