Figure 7. Model for the observed synthetic sick phenotype of Δmla with obgE*.

Mla mutants normally exhibit a 2-4X increase in OMV production, due in large part to the perturbed asymmetry of the OM (Roier et al., 2016). Additional evidence in E. coli suggests that fatty acids derived from OM phospholipase activity (PldA) stimulate lipid A biosynthesis (May and Silhavy, 2018). These factors result in an increased need for de novo fatty acid biosynthesis to contend with the rate of loss at the OM. Concurrently in the cytoplasm, the stringent response alarmone ppGpp has been shown to inhibit fatty acid biosynthesis (Heath et al., 1994). We know that Mla-null mutants (demonstrated here with dashed lines) with obgE* accumulate ppGpp at levels greater than that of WT (Figure 5, Figure 5—figure supplement 1). ObgE* could be acting through either partial inhibition of the hydrolysis of (p)ppGpp to GTP/GDP (red bars) or stimulating the hydrolysis of pppGpp to ppGpp (red arrow). The resultant accumulation of ppGpp would repress fatty acid biosynthesis despite the global need for increased biosynthesis due to OMV production.