Control of the committed step in lipopolysaccharide biosynthesis

Lipopolysaccharide (LPS) is an essential component of the outer membrane (OM) of most Gram-negative bacteria. It maintains envelope integrity and forms a permeability barrier that protects cells from environmental stress, host defenses, and many antibiotics. LPS biosynthesis must be tightly controlled to ensure proper OM assembly while preventing the toxic accumulation of intermediates. Central to this control is LpxC, a deacetylase that catalyzes the committed step in LPS biosynthesis and directs metabolic flux into the pathway. In Escherichia coli, LpxC abundance is primarily controlled by proteolysis mediated by the membrane-bound AAA+ protease FtsH. This process is regulated by two essential membrane proteins, LapB and YejM. LapB acts as an adaptor that promotes LpxC degradation, whereas YejM functions as an anti-adaptor that counteracts this activity. Through this regulatory network, signals from multiple stages of LPS biogenesis, along with inputs from other cell envelope biosynthetic pathways, are integrated to maintain LPS homeostasis. In addition to proteolytic control, new evidence suggests that LpxC enzymatic activity can also be modulated. Here, we summarize current understanding of the mechanisms governing LpxC regulation in E. coli and highlight unresolved questions. Further elucidation of these regulatory mechanisms may provide new opportunities for antibiotic development.