The Haemophilus influenzae HipBA toxin-antitoxin system adopts an unusual three-component regulatory mechanism

Abstract

Type II toxin-antitoxin (TA) systems encode two proteins: a toxin that inhibits cell growth and an antitoxin that neutralizes the toxin by direct intermolecular protein-protein interactions. The bacterial HipBA TA system is implicated in persister formation. The Haemophilus influenzae HipBATA system consists of a HipB antitoxin and a HipA toxin, the latter of which is split into two fragments, and here we investigate this novel three-component regulatory HipBA system. Structural and functional analysis revealed that HipA(N) corresponds to the N-terminal part of HipA from other bacteria and toxic HipA(C) is inactivated by HipA(N), not HipB. This study will be helpful in understanding the detailed regulatory mechanism of the HipBA(N+C) system, as well as why it is constructed as a three-component system.