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Nuclear effector proteins released by bacteria, oomycete, nematode, and fungi burden the global environment and crop yield. Microbial effectors are key weapons in the evolutionary arms race between plants and pathogens, vital in determining the success of pathogenic colonization. Secreted effectors undermine a multitude of host cellular processes depending on their target destination. Effectors are classified by their localization as either extracellular (apoplastic) or intracellular. Intracellular effectors can be further subclassified by their compartment such as the nucleus, cytoplasm or chloroplast. Nuclear effectors bring into question the role of the plant nucleus' intrinsic defence strategies and their vulnerability to effector‐based manipulation. Nuclear effectors interfere with multiple nuclear processes including the epigenetic regulation of the host chromatin, the impairment of the trans‐kingdom antifungal RNAi machinery, and diverse classes of immunity‐associated host proteins. These effector‐targeted pathways are widely conserved among different hosts and regulate a broad array of plant cellular processes. Thus, these nuclear sites constitute meaningful targets for effectors to subvert the plant defence system and acquire resources for pathogenic propagation. This review provides an extensive and comparative compilation of diverse plant microbe nuclear effector libraries, thereby highlighting the distinct and conserved mechanisms these effectors employ to modulate plant cellular processes for the pathogen's profit. This review provides an extensive comparison of plant microbe nuclear effectors, highlighting the mechanisms effectors employ to modulate plant cellular processes for the pathogen's benefit.

Metabolic engineering allows development of microbial strains efficiently producing chemicals and materials, but it requires much time, effort, and cost to make the strains industrially competitive. Systems metabolic engineering, which integrates tools and strategies of systems biology, synthetic biology, and evolutionary engineering with traditional metabolic engineering, has recently been used to facilitate development of high-performance strains. The past decade has witnessed this interdisciplinary strategy continuously being improved toward the development of industrially competitive overproducer strains. In this article, current trends in systems metabolic engineering including tools and strategies are reviewed, focusing on recent developments in selection of host strains, metabolic pathway reconstruction, tolerance enhancement, and metabolic flux optimization. Also, future challenges and prospects are discussed. Systems metabolic engineering, which integrated systems biology, synthetic biology, and evolutionary engineering with traditional metabolic engineering, is facilitating the development of high performance strains. More diverse microorganisms are being used as production host strains, supported by the new genetic tools and strategies. Recent advances in biosynthetic/semisynthetic design strategies are expanding the portfolio of products that can be produced biologically. Evolutionary engineering tools and strategies are facilitating the improvement of strain and enzyme performances. Advances in tools and strategies of omics, in silico metabolic simulation, genetic and genomic engineering, and high-throughput screening are accelerating optimization of metabolic fluxes for the enhanced production of target bioproducts.

Reductive genome evolution has purged many metabolic pathways from obligate intracellular Rickettsia ( Alphaproteobacteria ; Rickettsiaceae ). While some aspects of host-dependent rickettsial metabolism have been characterized, the array of host-acquired metabolites and their cognate transporters remains unknown. This dearth of information has thwarted efforts to obtain an axenic Rickettsia culture, a major impediment to conventional genetic approaches. Using phylogenomics and computational pathway analysis, we reconstructed the Rickettsia metabolic and transport network, identifying 51 host-acquired metabolites (only 21 previously characterized) needed to compensate for degraded biosynthesis pathways. In the absence of glycolysis and the pentose phosphate pathway, cell envelope glycoconjugates are synthesized from three imported host sugars, with a range of additional host-acquired metabolites fueling the tricarboxylic acid cycle. Fatty acid and glycerophospholipid pathways also initiate from host precursors, and import of both isoprenes and terpenoids is required for the synthesis of ubiquinone and the lipid carrier of lipid I and O-antigen. Unlike metabolite-provisioning bacterial symbionts of arthropods, rickettsiae cannot synthesize B vitamins or most other cofactors, accentuating their parasitic nature. Six biosynthesis pathways contain holes (missing enzymes); similar patterns in taxonomically diverse bacteria suggest alternative enzymes that await discovery. A paucity of characterized and predicted transporters emphasizes the knowledge gap concerning how rickettsiae import host metabolites, some of which are large and not known to be transported by bacteria. Collectively, our reconstructed metabolic network offers clues to how rickettsiae hijack host metabolic pathways. This blueprint for growth determinants is an important step toward the design of axenic media to rescue rickettsiae from the eukaryotic cell. IMPORTANCE A hallmark of obligate intracellular bacteria is the tradeoff of metabolic genes for the ability to acquire host metabolites. For species of Rickettsia , arthropod-borne parasites with the potential to cause serious human disease, the range of pilfered host metabolites is unknown. This information is critical for dissociating rickettsiae from eukaryotic cells to facilitate rickettsial genetic manipulation. In this study, we reconstructed the Rickettsia metabolic network and identified 51 host metabolites required to compensate patchwork Rickettsia biosynthesis pathways. Remarkably, some metabolites are not known to be transported by any bacteria, and overall, few cognate transporters were identified. Several pathways contain missing enzymes, yet similar pathways in unrelated bacteria indicate convergence and possible novel enzymes awaiting characterization. Our work illuminates the parasitic nature by which rickettsiae hijack host metabolism to counterbalance numerous disintegrated biosynthesis pathways that have arisen through evolution within the eukaryotic cell. This metabolic blueprint reveals what a Rickettsia axenic medium might entail. A hallmark of obligate intracellular bacteria is the tradeoff of metabolic genes for the ability to acquire host metabolites. For species of Rickettsia , arthropod-borne parasites with the potential to cause serious human disease, the range of pilfered host metabolites is unknown. This information is critical for dissociating rickettsiae from eukaryotic cells to facilitate rickettsial genetic manipulation. In this study, we reconstructed the Rickettsia metabolic network and identified 51 host metabolites required to compensate patchwork Rickettsia biosynthesis pathways. Remarkably, some metabolites are not known to be transported by any bacteria, and overall, few cognate transporters were identified. Several pathways contain missing enzymes, yet similar pathways in unrelated bacteria indicate convergence and possible novel enzymes awaiting characterization. Our work illuminates the parasitic nature by which rickettsiae hijack host metabolism to counterbalance numerous disintegrated biosynthesis pathways that have arisen through evolution within the eukaryotic cell. This metabolic blueprint reveals what a Rickettsia axenic medium might entail.

The human gut is inhabited by a complex and metabolically active microbial ecosystem. While many studies focused on the effect of individual microbial taxa on human health, their overall metabolic potential has been under-explored. Using whole-metagenome shotgun sequencing data in 1,004 twins, we first observed that unrelated subjects share, on average, almost double the number of metabolic pathways (82%) than species (43%). Then, using 673 blood and 713 faecal metabolites, we found metabolic pathways to be associated with 34% of blood and 95% of faecal metabolites, with over 18,000 significant associations, while species showed less than 3,000 associations. Finally, we estimated that the microbiome was involved in a dialogue between 71% of faecal, and 15% of blood, metabolites. This study underlines the importance of studying the microbial metabolic potential rather than focusing purely on taxonomy to find therapeutic and diagnostic targets, and provides a unique resource describing the interplay between the microbiome and the systemic and faecal metabolic environments. Here, the authors study the interplay between the microbiome and faecal and blood metabolome, and how the microbiome interacts in the dialogue between these metabolic compartments, identifying a key role for microbial functions and underscoring their relevance for microbiome therapeutic strategies.

Cellular activities are finely regulated by numerous signaling pathways to support specific functions of complex life processes. Viruses are obligate intracellular parasites. Cellular activities are finely regulated by numerous signaling pathways to support specific functions of complex life processes. Viruses are obligate intracellular parasites. Each step of viral replication is ultimately governed by the interaction of a virus with its host cells. Because of the demands of viral replication, the nutritional needs of virus-infected cells differ from those of uninfected cells. To improve their chances of survival and replication, viruses have evolved to commandeer cellular processes, including cell metabolism, augmenting these processes to support their needs. This article summarizes recent findings regarding virus-induced alterations to major cellular metabolic pathways focusing on how viruses modulate various signaling cascades to induce these changes. We begin with a general introduction describing the role played by signaling pathways in cellular metabolism. We then discuss how different viruses target these signaling pathways to reprogram host metabolism to favor the viral needs. We highlight the gaps in understanding metabolism-related virus-host interactions and discuss how studying these changes will enhance our understanding of fundamental processes involved in metabolic regulation. Finally, we discuss the potential to harness these processes to combat viral diseases, as well as other diseases, including metabolic disorders and cancers.

Peroxisomes are favorable platforms for organelle engineering, featuring abundant endogenous metabolites, optimal membrane permeability, frequent contacts with other organelles, efficient protein targeting signals, and many known organelle proliferation factors.Yeast peroxisome engineering has produced valuable biomolecules, such as biopolyesters, biofuels, terpenoids, alkaloids, antibiotics, and phytohormones.Plant peroxisome engineering has great potential in biomanufacturing and agriculture and adds values to improving environmental sustainability and food security.Approaches for improving the performance of heterologous pathways in peroxisomes include increasing peroxisomal abundance, coupling multiple subcellular compartments, maximizing precursor and cofactor supplies, uncovering the rate-limiting steps, and peroxisomal surface display of enzymes. Subcellular compartmentalization of metabolic pathways plays a crucial role in metabolic engineering. The peroxisome has emerged as a highly valuable and promising compartment for organelle engineering, particularly in the fields of biological manufacturing and agriculture. In this review, we summarize the remarkable achievements in peroxisome engineering in yeast, the industrially popular biomanufacturing chassis host, to produce various biocompounds. We also review progress in plant peroxisome engineering, a field that has already exhibited high potential in both biomanufacturing and agriculture. Moreover, we outline various experimentally validated strategies to improve the efficiency of engineered pathways in peroxisomes, as well as prospects of peroxisome engineering. Subcellular compartmentalization of metabolic pathways plays a crucial role in metabolic engineering. The peroxisome has emerged as a highly valuable and promising compartment for organelle engineering, particularly in the fields of biological manufacturing and agriculture. In this review, we summarize the remarkable achievements in peroxisome engineering in yeast, the industrially popular biomanufacturing chassis host, to produce various biocompounds. We also review progress in plant peroxisome engineering, a field that has already exhibited high potential in both biomanufacturing and agriculture. Moreover, we outline various experimentally validated strategies to improve the efficiency of engineered pathways in peroxisomes, as well as prospects of peroxisome engineering.

The production of bioactive plant compounds using microbial hosts is considered a safe, cost-competitive and scalable approach to their production. However, microbial production of some compounds like aromatic amino acid (AAA)-derived chemicals, remains an outstanding metabolic engineering challenge. Here we present the construction of a Saccharomyces cerevisiae platform strain able to produce high levels of p -coumaric acid, an AAA-derived precursor for many commercially valuable chemicals. This is achieved through engineering the AAA biosynthesis pathway, introducing a phosphoketalose-based pathway to divert glycolytic flux towards erythrose 4-phosphate formation, and optimizing carbon distribution between glycolysis and the AAA biosynthesis pathway by replacing the promoters of several important genes at key nodes between these two pathways. This results in a maximum p -coumaric acid titer of 12.5 g L −1 and a maximum yield on glucose of 154.9 mg g −1 . Microbial production of aromatic amino acid (AAA)-derived chemicals remains an outstanding metabolic engineering challenge. Here, the authors engineer baker’s yeast for high levels p -coumaric acid production by rewiring the central carbon metabolism and channeling more flux to the AAA biosynthetic pathway.

The study of microbiomes by sequencing has revealed a plethora of correlations between microbial community composition and various life-history characteristics of the corresponding host species. However, inferring causation from correlation is often hampered by the sheer compositional complexity of microbiomes, even in simple organisms. Synthetic communities offer an effective approach to infer cause-effect relationships in host-microbiome systems. Yet the available communities suffer from several drawbacks, such as artificial (thus non-natural) choice of microbes, microbe-host mismatch (e.g., human microbes in gnotobiotic mice), or hosts lacking genetic tractability. Here we introduce CeMbio, a simplified natural Caenorhabditis elegans microbiota derived from our previous meta-analysis of the natural microbiome of this nematode. The CeMbio resource is amenable to all strengths of the C. elegans model system, strains included are readily culturable, they all colonize the worm gut individually, and comprise a robust community that distinctly affects nematode life-history. Several tools have additionally been developed for the CeMbio strains, including diagnostic PCR primers, completely sequenced genomes, and metabolic network models. With CeMbio, we provide a versatile resource and toolbox for the in-depth dissection of naturally relevant host-microbiome interactions in C. elegans.

The clostridia are Firmicute bacterial commensals commonly found in the mammalian gut. Clostridia produce a range of metabolites that diffuse into the host's circulation and have been difficult to manipulate genetically, but Guo et al. successfully developed a CRISPR-Cas9 deletion system in Clostridium sporogenes (see the Perspective by Henke and Clardy). The authors used deletion mutants and mass spectrometry to elucidate clostridial synthesis of several different branched short-chain fatty acids (SCFAs), including isobutyrate, 2-methylbutyrate, and isovalerate. Germ-free mice colonized with mutants incapable of synthesizing SCFAs showed altered immunoglobulin A production. This finding potentially links bacterial SCFA production and host responses to the presence of the clostridia. Science , this issue p. eaav1282 ; see also p. 1309 Genetically knocking out the production of diffusible metabolites from intestinal commensals elucidates the host-bacterial interface. The gut microbiota produce hundreds of molecules that are present at high concentrations in the host circulation. Unraveling the contribution of each molecule to host biology remains difficult. We developed a system for constructing clean deletions in Clostridium spp., the source of many molecules from the gut microbiome. By applying this method to the model commensal organism Clostridium sporogenes , we knocked out genes for 10 C. sporogenes –derived molecules that accumulate in host tissues. In mice colonized by a C. sporogenes for which the production of branched short-chain fatty acids was knocked out, we discovered that these microbial products have immunoglobulin A–modulatory activity.

Metabolic engineering has emerged as an important tool for reconstructing heterologous isoprenoid metabolic pathways in microbial hosts. Here, we provide an overview of promising engineering strategies that have proven to be successful for the high-yield production of isoprenoids. Besides ‘conventional’ approaches, such as the ‘push–pull’ and protein engineering to optimize the isoprenoid flux and limited catalytic activity of enzymes, we review emerging strategies in the field, including compartmentalization between synthetic consortia members, novel bypass pathways for isoprenoid synthesis, cell-free systems, and improvement of the lipid content to overcome storage isoprenoid limitations. Pitfalls, along with lessons learned from the application of these strategies, will be addressed with the hope of guiding future efforts toward cost-effective and sustainable production of isoprenoids. Coculture systems can accommodate complex pathways that are difficult to engineer in a single cell. Mutualistic growth between the consortia members has been a successful strategy to maintain stable coculture systems.Protein engineering has been used as a complementary approach to increase the pathway flux in case there is a limited catalytic activity of the wild type enzymes.De novo entry pathways circumvent limitations associated with the native isoprenoid pathways, facilitating the optimization of cell growth and isoprenoid production.Enhanced formation of lipid bodies within the host leads to higher isoprenoid titers owing to increased storage capacity and solubility.The development of cell-free platforms is an emerging strategy offering manifold advantages, such as the precise control of reaction conditions and the absence of product toxicity.