Toxic component of a type II toxin-antitoxin (TA) system, first identified by mutations that increase production of persister cells, a fraction of cells that are phenotypic variants not killed by antibiotics, which lead to multidrug tolerance. Persistence may be ultimately due to global remodeling of the persister cell's ribosomes. Phosphorylates Glu-tRNA-ligase (AC P04805, gltX, on 'Ser-239') in vivo. Phosphorylation of GltX prevents it from being charged, leading to an increase in uncharged tRNA(Glu). This induces amino acid starvation and the stringent response via RelA/SpoT and increased (p)ppGpp levels, which inhibits replication, transcription, translation and cell wall synthesis, reducing growth and leading to persistence and multidrug resistance. Once the level of HipA exceeds a threshold cells become dormant, and the length of dormancy is determined by how much HipA levels exceed the threshold. The hipA7 mutation (a double G22S D291A mutation) leads to increased generation of persister cells (cells that survive antibiotic treatment) probably by entering into a dormant state, as well as cold-sensitivity. Wild-type cells produce persisters at a frequency of 10(-6) to 10(-5) whereas hipA7 cells produce about 100-fold more persisters. hipA7 decreases the affinity for antitoxin HipB, leading to increased HipA levels and persistence; depending on the protein level, can be toxic enough to reduce cell growth or even kill cells. Generation of persister cells requires (p)ppGpp as cells lacking relA or relA/spoT generate fewer or no persister cells respectively compared to hipA7. The toxic effect of HipA is neutralized by its cognate antitoxin HipB. Also neutralized by overexpression of gltX. With HipB acts as a corepressor for transcription of the hipBA promoter; binding of HipA-HipB to DNA induces a 70 degree bend. This brings together and dimerizes 2 HipA molecules, which distorts the promoter region, preventing sigma-factor binding; additionally HipA and HipB would physically prevent RNA core polymerase from contacting the -35 promoter box. May play a role in biofilm formation.
