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Journal Articles (Book Review) PLoS Genetics Year : 2020

A FAS solution to a DEAD case


CshA mutant cold sensitivity is a membrane problem In this issue of PLoS Genetics, Khemici and colleagues make the connection between two seemingly unrelated bacterial pathways, mRNA degradation and membrane biogenesis [1]. Research of the Linder lab in Geneva has long focused on the family of DEAD-box RNA helicases and their roles in RNA and DNA metabolism [2]. Here, the focus was on the Staphylococcus aureus CshA helicase, which has a general role in mRNA degradation via the RNA degradosome [3]. Khemici and colleagues used cold sensitivity of the cshA mutant to select for cold-tolerant mutant suppressors. This simple selection led to a surprising convergence of mutant genes, which mapped nearly exclusively to membrane lipid-related functions. Remarkably, most of the 82 sequenced mutations affected the fatty acid synthesis (FASII) pathway and precursor production. The authors navigated experimentally through numerous possibilities, which led them to uncover the basis for the membrane problem in cshA cold-sensitive mutants. They traced the problem to a failure to degrade the mRNA of pdh, encoding pyruvate dehydrogenase (PDH), which in aerobic conditions produces acetyl-CoA, a hub metabolite and FASII precursor (Fig 1). pdh mRNA accumulated in the cshA mutant compared to wild type (WT), reasonably predicting that acetyl-CoA pools were increased. In S. aureus, FASII uses acetyl-CoA to produce straight-chain saturated fatty acids (SCFA), which rigidify membranes. But acetyl-CoA competes with branched-chain acyl-CoA, the precursors for branchedchain fatty acids (BCFA), which fluidify membranes [4]. This SCFA to BCFA ratio is critical to membrane fluidity. Fatty acid extractions showed that SCFA to BCFA ratios were elevated in the cshA mutant compared to the WT strain. Less PDH (or more BCFA precursor production) in tested suppressor mutants restored this ratio to that of the WT, so that the membrane would regain fluidity. This highly documented study identifies pdh mRNA as the essential degradosome target for cold survival, and highlights the intimate connection between membrane state and central metabolism via acetyl-CoA. Why are FASII genes targets for cshA suppressors? Most cshA suppressors mapped to FASII or associated pathways. Mutations in FASII-related genes all presumably slow down phospholipid synthesis. Khemici and colleagues generalized this observation by showing that subinhibitory amounts of triclosan, which inhibits the FASII pathway protein FabI, suppressed cshA cold sensitivity. Their study also revealed that fakA, encoding a fatty acid kinase, was a cshA suppressor hotspot that corrected the SCFA to BCFA ratio. FakA depletion leads to free fatty acid accumulation that may modify S. aureus regulation and FASII activity and alter acetate utilization [5, 6]. How the slowdown of FASII synthesis adjusts fatty acid membrane composition and fluidity is a new open question arising from this work.
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hal-04309144 , version 1 (27-11-2023)



Alexandra Gruss. A FAS solution to a DEAD case. PLoS Genetics, 2020, 16, ⟨10.1371/journal.pgen.1008842⟩. ⟨hal-04309144⟩
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