Fig. 7: Regulatory circuit of ArcZ-mediated HMV regulation in K. pneumoniae.

Mucoid capsular polysaccharides are synthesized and translocated across membrane relying on protein products translated from the capsule gene cluster (e.g., Wza, Wzc, Wzi). The transcription of capsule genes is repressed by CRP via direct binding to the promoters; whereas their translation may be repressed by ArcZ at the RNA level. CRP activates the transcription of ArcZ precursor, which is further processed into a shorter mature ArcZ sRNA. Via direct RNA base-pairing interactions, ArcZ binds to the HMV-related mRNAs such as mlaA and fbp and inhibit their translation initiation. Reduced MlaA synthesis disrupts OM lipid asymmetry and homeostasis of phospholipid retrograde transport from outer leaflet, thereby interfering with the retention of capsular polysaccharides on the OM and proper level of HMV, abrogating Klebsiella virulence in mice. OM outer-membrane, IM inner-membrane, PG peptidoglycan, LPS Lipopolysaccharides.