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Chemical proteomic profiling reveals protein interactors of the alarmones diadenosine triphosphate and tetraphosphate.

ABSTRACT: The nucleotides diadenosine triphosphate (Ap₃A) and diadenosine tetraphosphate (Ap₄A) are formed in prokaryotic and eukaryotic cells. Since their concentrations increase significantly upon cellular stress, they are considered to be alarmones triggering stress adaptive processes. However, their cellular roles remain elusive. To elucidate the proteome-wide interactome of Ap₃A and Ap₄A and thereby gain insights into their cellular roles, we herein report the development of photoaffinity-labeling probes and their employment in chemical proteomics. We demonstrate that the identified Ap_nA interactors are involved in many fundamental cellular processes including carboxylic acid and nucleotide metabolism, gene expression, various regulatory processes and cellular response mechanisms and only around half of them are known nucleotide interactors. Our results highlight common functions of these Ap_nAs across the domains of life, but also identify those that are different for Ap₃A or Ap₄A. This study provides a rich source for further functional studies of these nucleotides and depicts useful tools for characterization of their regulatory mechanisms in cells.

SUBMITTER: Kruger L

PROVIDER: S-EPMC8490401 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Chemical proteomic profiling reveals protein interactors of the alarmones diadenosine triphosphate and tetraphosphate.

Krüger Lena L Albrecht Christoph J CJ Schammann Hannah K HK Stumpf Florian M FM Niedermeier Marie L ML Yuan Yizhi Y Stuber Katrin K Wimmer Josua J Stengel Florian F Scheffner Martin M Marx Andreas A

Nature communications 20211004 1

The nucleotides diadenosine triphosphate (Ap3A) and diadenosine tetraphosphate (Ap4A) are formed in prokaryotic and eukaryotic cells. Since their concentrations increase significantly upon cellular stress, they are considered to be alarmones triggering stress adaptive processes. However, their cellular roles remain elusive. To elucidate the proteome-wide interactome of Ap3A and Ap4A and thereby gain insights into their cellular roles, we herein report ...[more]

PMID: 34608152

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Project description:The opportunistic bacterial pathogen Pseudomonas aeruginosa causes a wide range of infections that are difficult to treat, largely because of the spread of antibiotic-resistant isolates. Antivirulence therapy, í.e. the use of drugs that inhibit the expression or activity of virulence factors, is currently considered an attractive strategy to reduce P. aeruginosa pathogenicity and complement antibiotic treatments. Because of the multifactorial nature of P. aeruginosa virulence and the broad arsenal of virulence factors this bacterium can produce, the regulatory networks that control the expression of multiple virulence traits have been extensively explored as potential targets for antivirulence drug development. The intracellular signaling molecule diadenosine tetraphosphate (Ap4A) has been reported to control stress resistance and virulence-related traits in some bacteria, but its role has not been investigated in P. aeruginosa so far. To fill this gap, we generated a mutant of the reference strain P. aeruginosa PAO1 that lacks the Ap4A-hydrolysing enzyme ApaH and, consequently, accumulates high intracellular levels of Ap4A. Phenotypic and transcriptomic analyses revealed that the lack of ApaH causes a drastic reduction in the expression of several virulence factors, including extracellular proteases, elastases, siderophores, and quorum sensing signal molecules. Accordingly, infection assays in plant and animal models demonstrated that ApaH-deficient cells are significantly impaired in infectivity and persistence in different hosts, including mice. Finally, deletion of apaH in P. aeruginosa clinical isolates demonstrated that the positive effect of ApaH on the production of virulence-related traits and on infectivity is conserved in P. aeruginosa. This study provides the first evidence that the Ap4A-hydrolysing enzyme ApaH is important for P. aeruginosa virulence, highlighting this protein as a novel potential target for antivirulence therapies against P. aeruginosa.

Dataset Information

Chemical proteomic profiling reveals protein interactors of the alarmones diadenosine triphosphate and tetraphosphate.

Publications

Chemical proteomic profiling reveals protein interactors of the alarmones diadenosine triphosphate and tetraphosphate.

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