•ETI affects de-novo synthesis of sphingolipids by altering the ceramides/dihydroceramides ratio•This effect is independent of the genotype and independent of CFTR rescue and functions•The effect is ...consistent with the inhibition of ceramide desaturase enzymes•Potential long-term safety concerns due to dihydrosphingolipid accumulation should be assessed
We report here how the triple combination of drugs elexacaftor/tezacaftor/ivacaftor (ETI) alters the balance of the de-novo synthethic pathway of sphingolipids in primary cells of human bronchial epithelium. The treatment with ETI roughly doubles the levels of dihydrosphingolipids, possibly by modulating the delta(4)-desaturase enzymes that convert dihydroceramides into ceramides. This appears to be an off-target effect of ETI, since it occurs in a genotype-independent manner, for both cystic fibrosis (CF) and non-CF subjects.
SUMMARY
Arabidopsis pathogen effector‐triggered immunity (ETI) is controlled by a family of three lipase‐like proteins (EDS1, PAD4, and SAG101) and two subfamilies of HET‐S/LOB‐B (HeLo)‐domain ...“helper” nucleotide‐binding/leucine‐rich repeats (ADR1s and NRG1s). EDS1‐PAD4 dimers cooperate with ADR1s, and EDS1‐SAG101 dimers with NRG1s, in two separate defense‐promoting modules. EDS1‐PAD4‐ADR1 and EDS1‐SAG101‐NRG1 complexes were detected in immune‐activated leaf extracts but the molecular determinants for specific complex formation and function remain unknown. EDS1 signaling is mediated by a C‐terminal EP domain (EPD) surface surrounding a cavity formed by the heterodimer. Here we investigated whether the EPDs of PAD4 and SAG101 contribute to EDS1 dimer functions. Using a structure‐guided approach, we undertook a comprehensive mutational analysis of Arabidopsis PAD4. We identify two conserved residues (Arg314 and Lys380) lining the PAD4 EPD cavity that are essential for EDS1‐PAD4–mediated pathogen resistance, but are dispensable for the PAD4‐mediated restriction of green peach aphid infestation. Positionally equivalent Met304 and Arg373 at the SAG101 EPD cavity are required for EDS1‐SAG101 promotion of ETI‐related cell death. In a PAD4 and SAG101 interactome analysis of ETI‐activated tissues, PAD4R314A and SAG101M304R EPD variants maintain interaction with EDS1 but lose association, respectively, with helper nucleotide‐binding/leucine‐rich repeats ADR1‐L1 and NRG1.1, and other immune‐related proteins. Our data reveal a fundamental contribution of similar but non‐identical PAD4 and SAG101 EPD surfaces to specific EDS1 dimer protein interactions and pathogen immunity.
Significance Statement
The molecular determinants for EDS1‐PAD4‐ADR1 and EDS1‐SAG101‐NRG1 complex formation and function remain unknown. In a PAD4 and SAG101 interactome analysis of ETI‐activated tissues, PAD4R314A and SAG101M304R EPD variants maintain interaction with EDS1 but lose association, respectively, with helper NLRs ADR1‐L1 and NRG1.1, and other immune‐related proteins, this reveals a fundamental contribution of similar but non‐identical PAD4 and SAG101 EPD surfaces to specific EDS1 dimer protein interactions and pathogen immunity.
After three decades of the amazing progress made on molecular studies of plant–microbe interactions (MPMI), we have begun to ask ourselves “what are the major questions still remaining?” as if the ...puzzle has only a few pieces missing. Such an exercise has ultimately led to the realization that we still have many more questions than answers. Therefore, it would be an impossible task for us to project a coherent “big picture” of the MPMI field in a single review. Instead, we provide our opinions on where we would like to go in our research as an invitation to the community to join us in this exploration of new MPMI frontiers.
We summarize recent progress and share our perspective in the areas of extracellular immunity, sensing of immunogenic signals by cell surface and intracellular immune receptors, heterogeneity of immune responses within tissues and cells, translational regulation as a critical layer of control in plant immune induction, and the role of the circadian clock in breaking the disease triangle in plants.
Candidate effectors from lettuce downy mildew (Bremia lactucae) enable high-throughput germplasm screening for the presence of resistance (R) genes. The nonhost species Lactuca saligna comprises a ...source of B. lactucae R genes that has hardly been exploited in lettuce breeding. Its cross-compatibility with the host species L. sativa enables the study of inheritance of nonhost resistance (NHR).
We performed transient expression of candidate RXLR effector genes from B. lactucae in a diverse Lactuca germplasm set. Responses to two candidate effectors (BLR31 and BLN08) were genetically mapped and tested for co-segregation with disease resistance.
BLN08 induced a hypersensitive response (HR) in 55% of the L. saligna accessions, but responsiveness did not co-segregate with resistance to Bl:24. BLR31 triggered an HR in 5% of the L. saligna accessions, and revealed a novel R gene providing complete B. lactucae race Bl:24 resistance. Resistant hybrid plants that were BLR31 nonresponsive indicated other unlinked R genes and/or nonhost QTLs.
We have identified a candidate avirulence effector of B. lactucae (BLR31) and its cognate R gene in L. saligna. Concurrently, our results suggest that R genes are not required for NHR of L. saligna.
Plants rely on multiple immune systems to protect themselves from pathogens. When pattern-triggered immunity (PTI)-the first layer of the immune response-is no longer effective as a result of ...pathogenic effectors, effector-triggered immunity (ETI) often provides resistance. In ETI, host plants directly or indirectly perceive pathogen effectors via resistance proteins and launch a more robust and rapid defense response. Resistance proteins are typically found in the form of nucleotide-binding and leucine-rich-repeat-containing receptors (NLRs). Upon effector recognition, an NLR undergoes structural change and associates with other NLRs. The dimerization or oligomerization of NLRs signals to downstream components, activates "helper" NLRs, and culminates in the ETI response. Originally, PTI was thought to contribute little to ETI. However, most recent studies revealed crosstalk and cooperation between ETI and PTI. Here, we summarize recent advancements in our understanding of the ETI response and its components, as well as how these components cooperate in the innate immune signaling pathways. Based on up-to-date accumulated knowledge, this review provides our current perspective of potential engineering strategies for crop protection.
Along with the emergence of green plants on this planet one billion years ago, the nucleotide binding site leucine-rich repeat (NLR) gene family originated and diverged into at least three ...subclasses. Two of them, with either characterized N-terminal toll/interleukin-1 receptor (TIR) or coiled-coil (CC) domain, serve as major types of immune receptor of effector-triggered immunity (ETI) in plants, whereas the one having a N-terminal Resistance to powdery mildew8 (RPW8) domain, functions as signal transfer component to them. In this review, we briefly summarized the history of identification of diverse NLR subclasses across Viridiplantae lineages during the establishment of NLR category, and highlighted recent advances on the evolution of NLR genes and several key downstream signal components under the background of ecological adaption.
•Much about NLR diversity and function are known in angiosperms but unknown in other plant lineages.•Plant NLR gene expansion and contraction are largely driven by ecological adaption.•Origin and divergence of EDS1 gene family reshaped seed plants ETI system.•NLR genes co-evolve with several key signal components.
•TRIKAFTA® tablets for children aged 6 years and older.•Difficulties swallowing tablets, eating disorders.•Clinical response of TRIKAFTA® when deconditioned.•Pharmacological assays of peak and ...residual plasma ETI levels.•TRIKAFTA®’s efficacy when deconditioned.
Plant immunity is the result of multiple distinct cellular processes cooperating with each other to generate immune responses. Autophagy is a conserved cellular recycling process and has ...well‐established roles in nutrient starvation responses and cellular homeostasis. Recently, the role of autophagy in immunity has become increasingly evident. However, our knowledge about plant autophagy remains limited, and how this fundamental cellular process is involved in plant immunity is still somewhat perplexing. Here, we summarize the current understanding of the positive and negative roles of autophagy in plant immunity and how different microbes exploit this process to their own advantage. The dualistic role of autophagy in plant immunity emphasizes that much remains to be explored in this area.
Significant insight into how a system for cellular degradation and recycling such as autophagy is involved in plant immunity has recently emerged. Many host pathways can positively or negatively modulate autophagy and the associated immune responses. Additionally, multiple plant microbes are able to manipulate autophagy. This review discusses recent advances in our understanding of the interplay between autophagy and plant defence.
Grain legumes play a crucial role in human nutrition and as a staple crop for low-income farmers in developing and underdeveloped nations, contributing to overall food security and agroecosystem ...services. Viral diseases are major biotic stresses that severely challenge global grain legume production. In this review, we discuss how exploring naturally resistant grain legume genotypes within germplasm, landraces, and crop wild relatives could be used as promising, economically viable, and eco-environmentally friendly solution to reduce yield losses. Studies based on Mendelian and classical genetics have enhanced our understanding of key genetic determinants that govern resistance to various viral diseases in grain legumes. Recent advances in molecular marker technology and genomic resources have enabled us to identify genomic regions controlling viral disease resistance in various grain legumes using techniques such as QTL mapping, genome-wide association studies, whole-genome resequencing, pangenome and 'omics' approaches. These comprehensive genomic resources have expedited the adoption of genomics-assisted breeding for developing virus-resistant grain legumes. Concurrently, progress in functional genomics, especially transcriptomics, has helped unravel underlying candidate gene(s) and their roles in viral disease resistance in legumes. This review also examines the progress in genetic engineering-based strategies, including RNA interference, and the potential of synthetic biology techniques, such as synthetic promoters and synthetic transcription factors, for creating viral-resistant grain legumes. It also elaborates on the prospects and limitations of cutting-edge breeding technologies and emerging biotechnological tools (e.g., genomic selection, rapid generation advances, and CRISPR/Cas9-based genome editing tool) in developing virus-disease-resistant grain legumes to ensure global food security.
Although childhood and adult abuse are more prevalent among patients with irritable bowel syndrome (IBS) than healthy individuals (controls), other types of early adverse life events (EALs) have not ...been well characterized. We investigated whether different types of EALs, before age 18 years, are more prevalent among patients with IBS, and the effects of sex and nongastrointestinal symptoms on the relationship between EALs and IBS.
EALs were evaluated in 294 IBS patients (79% women) and 435 controls (77% women) using the Early Trauma Inventory Self-Report Form, which delineates subcategories of general trauma and physical, emotional, and sexual abuse. Validated questionnaires assessed gastrointestinal, psychological, and somatic symptoms.
Compared with controls, IBS patients reported a higher prevalence of general trauma (78.5% vs 62.3%), physical punishment (60.6% vs 49.2%), emotional abuse (54.9% vs 27.0%), and sexual events (31.2% vs 17.9%) (all P < .001). These significant differences were observed mainly in women. Of the EAL domains, emotional abuse was the strongest predictor of IBS (P < .001). Eight of the 27 EAL items were significant (P < .001) and increased the odds of having IBS by 108% to 305%. Although EALs and psychological variables were related, EALs had an independent association with IBS (P = .04).
Various types of EALs are associated with the development of IBS-particularly among women. Psychological distress and somatic symptoms might contribute to this relationship. When appropriate, EALs and nongastrointestinal symptoms should be assessed in IBS patients.
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