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Intracellular calcium transients during plant-pathogen interactions are necessary early events leading to local and systemic acquired resistance. Salicylic acid, a critical messenger, is also required for both of these responses, but whether and how salicylic acid level is regulated by Ca(2+) signalling during plant-pathogen interaction is unclear. Here we report a mechanism connecting Ca(2+) signal to salicylic-acid-mediated immune response through calmodulin, AtSR1 (also known as CAMTA3), a Ca(2+)/calmodulin-binding transcription factor, and EDS1, an established regulator of salicylic acid level. Constitutive disease resistance and elevated levels of salicylic acid in loss-of-function alleles of Arabidopsis AtSR1 suggest that AtSR1 is a negative regulator of plant immunity. This was confirmed by epistasis analysis with mutants of compromised salicylic acid accumulation and disease resistance. We show that AtSR1 interacts with the promoter of EDS1 and represses its expression. Furthermore, Ca(2+)/calmodulin-binding to AtSR1 is required for suppression of plant defence, indicating a direct role for Ca(2+)/calmodulin in regulating the function of AtSR1. These results reveal a previously unknown regulatory mechanism linking Ca(2+) signalling to salicylic acid level.

Intracellular calcium transients during plant-pathogen interactions are necessary early events leading to local and systemic acquired resistance. Salicylic acid, a critical messenger, is also required for both of these responses, but whether and how salicylic acid level is regulated by Ca2+ signalling during plant-pathogen interaction is unclear. Here we report a mechanism connecting Ca2+ signal to salicylic-acid-mediated immune response through calmodulin, AtSR1 (also known as CAMTA3), a Ca2+/calmodulin-binding transcription factor, and EDS1, an established regulator of salicylic acid level. Constitutive disease resistance and elevated levels of salicylic acid in loss-of-function alleles of Arabidopsis AtSR1 suggest that AtSR1 is a negative regulator of plant immunity. This was confirmed by epistasis analysis with mutants of compromised salicylic acid accumulation and disease resistance. We show that AtSR1 interacts with the promoter of EDS1 and represses its expression. Furthermore, Ca2+/calmodulin-binding to AtSR1 is required for suppression of plant defence, indicating a direct role for Ca2+/calmodulin in regulating the function of AtSR1. These results reveal a previously unknown regulatory mechanism linking Ca2+ signalling to salicylic acid level.

Intracellular calcium transients during plant-pathogen interactions are necessary early events leading to local and systemic acquired resistance (1). Salicylic acid, a critical messenger, is also required for both of these responses (2,3), but whether and how salicylic acid level is regulated by [Ca.sup.2+] signalling during plant-pathogen interaction is unclear. Here we report a mechanism connecting [Ca.sup.2+] signal to salicylic-acid-mediated immune response through calmodulin, AtSR1 (also known as CAMTA3), a [Ca.sup.2+]/calmodulin-binding transcription factor, and EDS1, an established regulator of salicylic acid level. Constitutive disease resistance and elevated levels of salicylic acid in loss-of-function alleles of Arabidopsis AtSR1 suggest that AtSR1 is a negative regulator of plant immunity. This was confirmed by epistasis analysis with mutants of compromised salicylic acid accumulation and disease resistance. We show that AtSR1 interacts with the promoter of EDS1 and represses its expression. Furthermore, [Ca.sup.2+]/calmodulin-binding to AtSR1 is required for suppression of plant defence, indicating a direct role for [Ca.sup.2+]/ calmodulin in regulating the function of AtSR1. These results reveal a previously unknown regulatory mechanism linking [Ca.sup.2+] signalling to salicylic acid level.

Intracellular calcium transients during plant-pathogen interactions are necessary early events leading to local and systemic acquired resistance. Salicylic acid, a critical messenger, is also required for both of these responses, but whether and how salicylic acid level is regulated by Ca super(2+) signalling during plant-pathogen interaction is unclear. Here we report a mechanism connecting Ca super(2+) signal to salicylic-acid-mediated immune response through calmodulin, AtSR1 (also known as CAMTA3), a Ca super(2+)/calmodulin-binding transcription factor, and EDS1, an established regulator of salicylic acid level. Constitutive disease resistance and elevated levels of salicylic acid in loss-of-function alleles of Arabidopsis AtSR1 suggest that AtSR1 is a negative regulator of plant immunity. This was confirmed by epistasis analysis with mutants of compromised salicylic acid accumulation and disease resistance. We show that AtSR1 interacts with the promoter of EDS1 and represses its expression. Furthermore, Ca super(2+)/calmodulin-binding to AtSR1 is required for suppression of plant defence, indicating a direct role for Ca super(2+)/calmodulin in regulating the function of AtSR1. These results reveal a previously unknown regulatory mechanism linking Ca super(2+) signalling to salicylic acid level.

Intracellular calcium transients during plant-pathogen interactions are necessary early events leading to local and systemic acquired resistance1. Salicylic acid, a critical messenger, is also required for both of these responses2,3, but whether and how salicylic acid level is regulated by Ca^sup 2+^ signalling during plant-pathogen interaction is unclear. Here we report a mechanism connecting Ca^sup 2+^ signal to salicylic-acid-mediated immune response through calmodulin, AtSR1 (also known as CAMTA3), a Ca^sup 2+^/calmodulin-binding transcription factor, and EDS1, an established regulator of salicylic acid level. Constitutive disease resistance and elevated levels of salicylic acid in loss-of-function alleles of Arabidopsis AtSR1 suggest that AtSR1 is a negative regulator of plant immunity. This was confirmed by epistasis analysis with mutants of compromised salicylic acid accumulation and disease resistance. We show that AtSR1 interacts with the promoter of EDS1 and represses its expression. Furthermore, Ca^sup 2+^/calmodulin-binding to AtSR1 is required for suppression of plant defence, indicating a direct role for Ca^sup 2+^/calmodulin in regulating the function of AtSR1. These results reveal a previously unknown regulatory mechanism linking Ca^sup 2+^ signalling to salicylic acid level. [PUBLICATION ABSTRACT]

Patients with EGFR- mutant non-small-cell lung cancer (NSCLC) have significantly benefited from the use of EGFR tyrosine kinase inhibitors (TKIs). However, long-term efficacy of these therapies is limited due to de novo resistance (~30%) as well as acquired resistance. Epithelial–mesenchymal transition transcription factors (EMT-TFs), have been identified as drivers of EMT-mediated resistance to EGFR TKIs, however, strategies to target EMT-TFs are lacking. As the third generation EGFR TKI, osimertinib, has now been adopted in the first-line setting, the frequency of T790M mutations will significantly decrease in the acquired resistance setting. Previously less common mechanisms of acquired resistance to first generation EGFR TKIs including EMT are now being observed at an increased frequency after osimertinib. Importantly, there are no other FDA approved targeted therapies after progression on osimertinib. Here, we investigated a novel strategy to overcome EGFR TKI resistance through targeting the EMT-TF, TWIST1, in EGFR- mutant NSCLC. We demonstrated that genetic silencing of TWIST1 or treatment with the TWIST1 inhibitor, harmine, resulted in growth inhibition and apoptosis in EGFR- mutant NSCLC. TWIST1 overexpression resulted in erlotinib and osimertinib resistance in EGFR -mutant NSCLC cells. Conversely, genetic and pharmacological inhibition of TWIST1 in EGFR TKI-resistant EGFR- mutant cells increased sensitivity to EGFR TKIs. TWIST1-mediated EGFR TKI resistance was due in part to TWIST1 suppression of transcription of the pro-apoptotic BH3-only gene, BCL2L11 (BIM), by directly binding to BCL2L11 intronic regions and promoter. As such, pan-BCL2 inhibitor treatment overcame TWIST1-mediated EGFR TKI resistance and were more effective in the setting of TWIST1 overexpression. Finally, in a mouse model of autochthonous EGFR -mutant lung cancer, Twist1 overexpression resulted in erlotinib resistance and suppression of erlotinib-induced apoptosis. These studies establish TWIST1 as a driver of resistance to EGFR TKIs and provide rationale for use of TWIST1 inhibitors or BCL2 inhibitors as means to overcome EMT-mediated resistance to EGFR TKIs.

Comparative studies suggest remarkable similarities among food webs across habitats, including systematic changes in their structure with diversity and complexity (scale-dependence). However, historic aboveground terrestrial food webs (ATFWs) have coarsely grouped plants and insects such that these webs are generally small, and herbivory is disproportionately underrepresented compared to vertebrate predator-prey interactions. Furthermore, terrestrial herbivory is thought to be structured by unique processes compared to size-structured feeding in other systems. Here, we present the richest ATFW to date, including ∼580,000 feeding links among ∼3,800 taxonomic species, sourced from ∼27,000 expert-vetted interaction records annotated as feeding upon one of six different resource types: leaves, flowers, seeds, wood, prey, and carrion. By comparison to historical ATFWs and null ecological hypotheses, we show that our temperate forest web displays a potentially unique structure characterized by two properties: a) a large fraction of carnivory interactions dominated by a small number of hyper-generalist, opportunistic bird and bat predators, and b) a smaller fraction of herbivory interactions dominated by a hyper-rich community of insects with variably-sized but highly-specific diets. We attribute our findings to the large-scale, even resolution of vertebrate, insect, and plant guilds in our food web.