Salmonella enterica Serovar Typhimurium Uses PbgA/YejM To Regulate Lipopolysaccharide Assembly during Bacteremia

Cian, Melina B.; Giordano, Nicole; Masilamani, Revathi; Minor, Keaton E.; Dalebroux, Zachary D.

doi:10.1128/iai.00758-19

Cited by 41 publications

(74 citation statements)

References 86 publications

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“…Overall, our findings indicate that YejM inhibits the YciM/FtsH protease complex, which is responsible for degrading LpxC. OM defects associated with truncation of YejM in Salmonella enterica serovar Typhimurium can also be suppressed by mutations in yciM, lpxC, and ftsH (38), suggesting that control of LpxC degradation may be a conserved function of YejM.…”

Section: Discussionmentioning

confidence: 66%

YejM Modulates Activity of the YciM/FtsH Protease Complex To Prevent Lethal Accumulation of Lipopolysaccharide

Guest

Guerra

Wissler

et al. 2020

mBio

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Lipopolysaccharide (LPS) is an essential glycolipid present in the outer membrane (OM) of many Gram-negative bacteria. Balanced biosynthesis of LPS is critical for cell viability; too little LPS weakens the OM, while too much LPS is lethal. In Escherichia coli, this balance is maintained by the YciM/FtsH protease complex, which adjusts LPS levels by degrading the LPS biosynthesis enzyme LpxC. Here, we provide evidence that activity of the YciM/FtsH protease complex is inhibited by the essential protein YejM. Using strains in which LpxC activity is reduced, we show that yciM is epistatic to yejM, demonstrating that YejM acts upstream of YciM to prevent toxic overproduction of LPS. Previous studies have shown that this toxicity can be suppressed by deleting lpp, which codes for a highly abundant OM lipoprotein. It was assumed that deletion of lpp restores lipid balance by increasing the number of acyl chains available for glycerophospholipid biosynthesis. We show that this is not the case. Rather, our data suggest that preventing attachment of lpp to the peptidoglycan sacculus allows excess LPS to be shed in vesicles. We propose that this loss of OM material allows continued transport of LPS to the OM, thus preventing lethal accumulation of LPS within the inner membrane. Overall, our data justify the commitment of three essential inner membrane proteins to avoid toxic over- or underproduction of LPS. IMPORTANCE Gram-negative bacteria are encapsulated by an outer membrane (OM) that is impermeable to large and hydrophobic molecules. As such, these bacteria are intrinsically resistant to several clinically relevant antibiotics. To better understand how the OM is established or maintained, we sought to clarify the function of the essential protein YejM in Escherichia coli. Here, we show that YejM inhibits activity of the YciM/FtsH protease complex, which regulates synthesis of the essential OM glycolipid lipopolysaccharide (LPS). Our data suggest that disrupting proper communication between LPS synthesis and transport to the OM leads to accumulation of LPS within the inner membrane (IM). The lethality associated with this event can be suppressed by increasing OM vesiculation. Our research has identified a completely novel signaling pathway that we propose coordinates LPS synthesis and transport.

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Section: Discussionmentioning

confidence: 66%

YejM Modulates Activity of the YciM/FtsH Protease Complex To Prevent Lethal Accumulation of Lipopolysaccharide

Guest

Guerra

Wissler

et al. 2020

mBio

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“…In E. coil , a dominant allele of mlaA , which encodes the OM lipoprotein component of the Mla system, causes symmetrical microdomains to form within the OM ( Sutterlin et al, 2016 ). Perturbing asymmetry results in signal transduction across the periplasm and a lipid-mediated regulatory mechanism that controls LPS biosynthesis ( Cian et al, 2019 ; May and Silhavy, 2018 ). Accordingly, we hypothesized that the Mla system and the suppressive insertion might influence the LOS levels for A. baumannii .…”

Section: Resultsmentioning

confidence: 99%

Modulating Isoprenoid Biosynthesis Increases Lipooligosaccharides and Restores Acinetobacter baumannii Resistance to Host and Antibiotic Stress

et al. 2020

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SUMMARY Acinetobacter baumannii is a leading cause of ventilator-associated pneumonia and a critical threat due to multidrug resistance. The A. baumannii outer membrane is an asymmetric lipid bilayer composed of inner leaflet glycerophospholipids and outer leaflet lipooligosaccharides. Deleting mlaF of the maintenance of lipid asymmetry (Mla) system causes A. baumannii to become more susceptible to pulmonary surfactants and antibiotics and decreases bacterial survival in the lungs of mice. Spontaneous suppressor mutants isolated from infected mice contain an IS Aba11 insertion upstream of the ispB initiation codon, an essential isoprenoid biosynthesis gene. The insertion restores antimicrobial resistance and virulence to Δ mlaF . The suppressor strain increases lipooligosaccharides, suggesting that the mechanism involves balancing the glycerophospholipids/lipooligosaccharides ratio on the bacterial surface. An identical insertion exists in an extensively drug-resistant A. baumannii isolate, demonstrating its clinical relevance. These data show that the stresses bacteria encounter during infection select for genomic rearrangements that increase resistance to antimicrobials.

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“…According to a recent study, YejM plays a phoPQ-dependent role in lipopolysaccharide assembly, that requires presence of an intact YejM. Absence of YejM PD leads to accumulation of lipid A-core molecules lacking O-antigen in the OM, as well as a decrease in amount of cyclopropanated fatty acids in the OM 23 . These observations further strengthen the hypothesis that YejM influences LPS assembly and is involved in lipid homeostasis of bacterial membrane.…”

Section: Discussionmentioning

confidence: 99%

“…The essential gene yejM was discovered in E. coli and S. typhimurium 21,22 . The homologue in S. typhimurium was termed pbgA (PhoPQ-barrier gene A) and plays a crucial role in increased cardiolipin levels in the OM 22 , and linked to lipopolysaccharide (LPS) assembly defects in deletion mutants, specifically manifested by an increase in levels of lipid A core molecules, in a PhoPQ-dependent manner 23 . yejM codes for an inner membrane protein with five predicted helical transmembrane domain (5TM), followed by a positively charged linker region and a C-terminal periplasmic domain (PD) (Figure 1a).…”

Section: Introductionmentioning

confidence: 99%

New functional identity of the essential inner membrane protein YejM: the cardiolipin translocator is also a metalloenzyme

Gabale

Palomino

Kim

et al. 2020

Preprint

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Recent recurrent outbreaks of Gram-negative bacteria show the critical need to target essential bacterial mechanisms to fight the increase of antibiotic resistance. Pathogenic Gram-negative bacteria have developed several strategies to protect themselves against the host immune response and antibiotics. One strategy is to remodel the outer membrane where several genes are involved. yejM was discovered as an essential gene in E. coli and S. typhimurium that plays a critical role in their virulence by changing the outer membrane permeability by translocating and increasing the cardiolipin lipid concentration. How the inner membrane protein YejM with its periplasmic domain acts as a cardiolipin translocator remains unknown. Despite overwhelming structural similarity of the periplasmic domains of two YejM homologues with hydrolases like arylsulfatases, no enzymatic activity has been reported for YejM. Our studies reveal an intact active site with bound metal ions in the structure of YejM periplasmic domain. Furthermore, we show that YejM has a phosphatase activity that is dependent on the presence of magnesium ions and is linked to its cardiolipin translocation properties. Understanding the molecular mechanism by which YejM is involved in OM remodeling will help to identify a new drug target in the fight against the increased antibiotic resistance.

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Salmonella enterica Serovar Typhimurium Uses PbgA/YejM To Regulate Lipopolysaccharide Assembly during Bacteremia

Cited by 41 publications

References 86 publications

YejM Modulates Activity of the YciM/FtsH Protease Complex To Prevent Lethal Accumulation of Lipopolysaccharide

YejM Modulates Activity of the YciM/FtsH Protease Complex To Prevent Lethal Accumulation of Lipopolysaccharide

Modulating Isoprenoid Biosynthesis Increases Lipooligosaccharides and Restores Acinetobacter baumannii Resistance to Host and Antibiotic Stress

New functional identity of the essential inner membrane protein YejM: the cardiolipin translocator is also a metalloenzyme

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