FtsH-Mediated Coordination of Lipopolysaccharide Biosynthesis in Escherichia coli Correlates with the Growth Rate and the Alarmone (p)ppGpp

Schäkermann, Sina; Langklotz, Sina; Narberhaus, Franz

doi:10.1128/jb.02134-12

Cited by 52 publications

(80 citation statements)

References 80 publications

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“…Consistent with the cellular demand, degradation of LpxC negatively correlates with the growth rate, i.e. the enzyme is stable during fast growth and rapidly degraded when cells grow slowly ( Figure 1B) (Schäkermann et al, 2013). A factor that is involved in growth-rate dependent turn-over of LpxC is the alarmone (p)ppGpp (Schäkermann et al, 2013).…”

Section: Conditional Proteolysis Of Selected Ftsh Substrates Lpxc Thmentioning

confidence: 79%

“…the enzyme is stable during fast growth and rapidly degraded when cells grow slowly ( Figure 1B) (Schäkermann et al, 2013). A factor that is involved in growth-rate dependent turn-over of LpxC is the alarmone (p)ppGpp (Schäkermann et al, 2013). (p)ppGpp, best known for its role in the stringent response, is involved in regulating many processes in response to various stress and starvation signals (Potrykus and Cashel, 2008;Gaca et al, 2015).…”

Section: Conditional Proteolysis Of Selected Ftsh Substrates Lpxc Thmentioning

confidence: 99%

“…In the absence of the signaling molecule, proteolysis of LpxC is mis-regulated. In stark contrast to the situation in wild-type cells, degradation is fast when the (p)ppGpp-negative mutant grows rapidly and is slow when it grows poorly (Schäkermann et al, 2013). The mechanism of alarmone-controlled LpxC degradation is under investigation.…”

Section: Conditional Proteolysis Of Selected Ftsh Substrates Lpxc Thmentioning

confidence: 99%

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When, how and why? Regulated proteolysis by the essential FtsH protease in Escherichia coli

Bittner

Arends

Narberhaus

2017

Biological Chemistry

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Cellular proteomes are dynamic and adjusted to permanently changing conditions by ATP-fueled proteolytic machineries. Among the five AAA + proteases in Escherichia coli FtsH is the only essential and membraneanchored metalloprotease. FtsH is a homohexamer that uses its ATPase domain to unfold and translocate substrates that are subsequently degraded without the need of ATP in the proteolytic chamber of the protease domain. FtsH eliminates misfolded proteins in the context of general quality control and properly folded proteins for regulatory reasons. Recent trapping approaches have revealed a number of novel FtsH substrates. This review summarizes the substrate diversity of FtsH and presents details on the surprisingly diverse recognition principles of three well-characterized substrates: LpxC, the key enzyme of lipopolysaccharide biosynthesis; RpoH, the alternative heat-shock sigma factor and YfgM, a bifunctional membrane protein implicated in periplasmic chaperone functions and cytoplasmic stress adaptation.

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Section: Conditional Proteolysis Of Selected Ftsh Substrates Lpxc Thmentioning

confidence: 79%

Section: Conditional Proteolysis Of Selected Ftsh Substrates Lpxc Thmentioning

confidence: 99%

Section: Conditional Proteolysis Of Selected Ftsh Substrates Lpxc Thmentioning

confidence: 99%

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When, how and why? Regulated proteolysis by the essential FtsH protease in Escherichia coli

Bittner

Arends

Narberhaus

2017

Biological Chemistry

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“…S2F). LpxC is known to be regulated by FtsH-mediated proteolysis (23), and thus we suspect that the mlaA* mutation stabilizes the LpxC protein (likely indirectly), resulting in increased synthesis and assembly of LPS in this mutant background.…”

Section: Resultsmentioning

confidence: 99%

Disruption of lipid homeostasis in the Gram-negative cell envelope activates a novel cell death pathway

Sutterlin

Shi

May

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

160

197

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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 celldivision 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.

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“…The alarmone (p)ppGpp is involved in the regulation of fatty acids and lipopolysaccharide synthesis in E. coli (5,51,52). Recently, it was shown that c-di-GMP binds to a transcription factor, LtmA, that regulates the expression of genes involved in lipid transport in M. smegmatis (21).…”

Section: Figmentioning

confidence: 99%

Novel Functions of (p)ppGpp and Cyclic di-GMP in Mycobacterial Physiology Revealed by Phenotype Microarray Analysis of Wild-Type and Isogenic Strains of Mycobacterium smegmatis

Gupta

Kasetty

Chatterji

2015

Appl Environ Microbiol

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The bacterial second messengers (p)ppGpp and bis-(3=-5=)-cyclic dimeric GMP (c-di-GMP) regulate important functions, such as transcription, virulence, biofilm formation, and quorum sensing. In mycobacteria, they regulate long-term survival during starvation, pathogenicity, and dormancy. Recently, a Pseudomonas aeruginosa strain lacking (p)ppGpp was shown to be sensitive to multiple classes of antibiotics and defective in biofilm formation. We were interested to find out whether Mycobacterium smegmatis strains lacking the gene for either (p)ppGpp synthesis (⌬rel Msm ) or c-di-GMP synthesis (⌬dcpA) would display similar phenotypes. We used phenotype microarray technology to compare the growth of the wild-type and the knockout strains in the presence of several antibiotics. Surprisingly, the ⌬rel Msm and ⌬dcpA strains showed enhanced survival in the presence of many antibiotics, but they were defective in biofilm formation. These strains also displayed altered surface properties, like impaired sliding motility, rough colony morphology, and increased aggregation in liquid cultures. Biofilm formation and surface properties are associated with the presence of glycopeptidolipids (GPLs) in the cell walls of M. smegmatis. Thin-layer chromatography analysis of various cell wall fractions revealed that the levels of GPLs and polar lipids were reduced in the knockout strains. As a result, the cell walls of the knockout strains were significantly more hydrophobic than those of the wild type and the complemented strains. We hypothesize that reduced levels of GPLs and polar lipids may contribute to the antibiotic resistance shown by the knockout strains. Altogether, our data suggest that (p)ppGpp and c-di-GMP may be involved in the metabolism of glycopeptidolipids and polar lipids in M. smegmatis. N ucleotide-based second messengers regulate various biological processes in all domains of life. Pentaphosphate guanosine (pppGpp) or tetraphosphate guanosine (ppGpp), collectively referred to as (p)ppGpp, and bis-(3=-5=)-cyclic dimeric GMP (cdi-GMP) are two such bacterial second messengers (1, 2). The alarmone (p)ppGpp is synthesized when bacteria are stressed or starved and regulates important processes, like stringent response, quorum sensing, virulence, and biofilm formation (2-5). In mycobacteria, (p)ppGpp is synthesized and broken down by the dual-function enzyme Rel, encoded by the rel gene (6). The Mycobacterium smegmatis rel gene knockout (⌬rel Msm ) strain is compromised for long-term survival during nutrient starvation and progressive hypoxia (7). Similarly, Mycobacterium tuberculosis lacking the Rel Mtb protein has reduced long-term survival in the lungs of mice and in a mouse hypoxic granuloma model and fails to form tubercle lesions in a guinea pig model of infection (8-11). Both the M. tuberculosis and M. smegmatis genomes encode a second (p)ppGpp synthetase called small alarmone synthetase (12, 13). However, its role in mycobacterial physiology has not been completely elucidated.The signaling nucleotide c-di-GMP is s...

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FtsH-Mediated Coordination of Lipopolysaccharide Biosynthesis in Escherichia coli Correlates with the Growth Rate and the Alarmone (p)ppGpp

Cited by 52 publications

References 80 publications

When, how and why? Regulated proteolysis by the essential FtsH protease in Escherichia coli

When, how and why? Regulated proteolysis by the essential FtsH protease in Escherichia coli

Disruption of lipid homeostasis in the Gram-negative cell envelope activates a novel cell death pathway

Novel Functions of (p)ppGpp and Cyclic di-GMP in Mycobacterial Physiology Revealed by Phenotype Microarray Analysis of Wild-Type and Isogenic Strains of Mycobacterium smegmatis

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