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2016 ; 113
(11
): E1565-74
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Disruption of lipid homeostasis in the Gram-negative cell envelope activates a
novel cell death pathway
#MMPMID26929379
Sutterlin HA
; Shi H
; May KL
; Miguel A
; Khare S
; Huang KC
; Silhavy TJ
Proc Natl Acad Sci U S A
2016[Mar]; 113
(11
): E1565-74
PMID26929379
show ga
Gram-negative bacteria balance synthesis of the outer membrane (OM), cell wall,
and cytoplasmic contents during growth via unknown mechanisms. Here, we show that
a dominant mutation (designated mlaA*, maintenance of lipid asymmetry) that
alters MlaA, a lipoprotein that removes phospholipids from the outer leaflet of
the OM of Escherichia coli, increases OM permeability, lipopolysaccharide levels,
drug sensitivity, and cell death in stationary phase. Surprisingly, single-cell
imaging revealed that death occurs after protracted loss of OM material through
vesiculation and blebbing at cell-division sites and compensatory shrinkage of
the inner membrane, eventually resulting in rupture and slow leakage of
cytoplasmic contents. The death of mlaA* cells was linked to fatty acid depletion
and was not affected by membrane depolarization, suggesting that lipids flow from
the inner membrane to the OM in an energy-independent manner. Suppressor analysis
suggested that the dominant mlaA* mutation activates phospholipase A, resulting
in increased levels of lipopolysaccharide and OM vesiculation that ultimately
undermine the integrity of the cell envelope by depleting the inner membrane of
phospholipids. This novel cell-death pathway suggests that balanced synthesis
across both membranes is key to the mechanical integrity of the Gram-negative
cell envelope.