Biology subjects

Suarez, J.

Publications and source records attributed to Suarez, J..

4 recordsLinked to original sources

bioRxiv2026

Selective autophagy promotes bacterial immunity under warming through NBR1-dependent regulation of ABI5

Elevated temperatures compromise plant immunity and increase susceptibility to bacterial pathogens through extensive reprogramming of hormone signaling pathways. Although autophagy contributes to both stress adaptation and pathogen defense, its role in hormone-dependent immune regulation under warm conditions remains unclear. Here, we investigated the contribution of NBR1 (NEIGHBOR OF BRCA1 GENE 1)-mediated selective autophagy to Arabidopsis immunity against Pseudomonas cannabina pv. alisalensis at elevated temperature. Bacterial infection under warming enhanced autophagic flux and promoted NBR1 turnover, indicating increased autophagic activity. Analysis of atg5 and nbr1 mutants, and NBR1-overexpressing lines, demonstrated that both core autophagy and NBR1-mediated selective autophagy contribute to bacterial immunity under warm conditions. Hormone and gene expression analyses indicated that NBR1 negatively regulates abscisic acid (ABA)-associated transcriptional responses during infection, while salicylic acid signaling was largely unaffected. Mechanistically, NBR1 physically associated with the ABA-responsive transcription factor ABI5 (ABA INSENSITIVE 5) and promoted its autophagy-dependent turnover in planta. ABI5 turnover was strongly reduced under warm conditions, leading to its accumulation in nbr1 and atg5 plants. Consistent with a functional role for ABI5 in this phenotype, genetic disruption of ABI5 largely reversed the increased susceptibility of nbr1 mutants at elevated temperature, whereas ABI5 overexpression increased susceptibility to bacterial infection. Together, our results identify NBR1-mediated selective autophagy as a regulatory mechanism that restrains ABA-associated susceptibility through the autophagy-dependent turnover of ABI5. These findings reveal a previously unrecognized connection between selective autophagy and ABA-dependent immune regulation and identify NBR1-mediated ABI5 turnover as a temperature-dependent mechanism that prevents stronger bacterial susceptibility under warm conditions.

plant biology↗

bioRxiv2026

A Translational Model of MASLD-Associated HFpEF Defines Mitochondrial Dysfunction and Cardiac Plasticity During Disease Progression and Regression

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are strongly linked to cardiac dysfunction, particularly, heart failure with preserved ejection fraction (HFpEF), yet the mechanisms underlying this association remain unclear because robust integrative preclinical models are lacking and the liver and heart are rarely studied as a coordinated system. Here we show that Alms1-/- (Foz/Foz) mice fed a Western diet develop MASH with advanced liver fibrosis accompanied by a HFpEF-like phenotype characterized by left ventricular hypertrophy, impaired cardiomyocyte contractility, reduced {beta}-adrenergic reserve, elevated BNP, and increased mortality despite ejection fraction >50%. Liver fibrosis emerged as a parameter strongly associated with the cardiac dysfunction. Remarkably, dietary reversal improved hepatic architecture, normalized cardiac function, and improved survival, revealing marked plasticity of the liver-heart axis. Analyses of left ventricular (LV) remodeling revealed mitochondrial dysfunction, altered substrate utilization, and extracellular matrix remodeling in the LV, with consistent concordance to human HFpEF transcriptomic signatures. Ultrastructural studies confirmed mitochondrial injury and sarcomeric disorganization, linking metabolic failure to impaired cardiomyocyte performance. Together, these findings identify mitochondrial dysfunction as an important feature of MASLD-associated HFpEF-like cardiac dysfunction and establish the Foz/Foz model as a powerful platform for investigating pathophysiological pathways linking metabolic liver disease to cardiac dysfunction and for testing mechanism-based therapeutic strategies. STRUCTURED ABSTRACTO_ST_ABSBackgroundC_ST_ABSMetabolic dysfunction associated steatotic liver disease (MASLD) and its advanced form, MASH, are closely linked to cardiac dysfunction, particularly heart failure with preserved ejection fraction (HFpEF). However, the mechanisms underlying MASLD-associated HFpEF and its reversibility remain poorly understood, largely due to the lack of robust preclinical models. Here, we established a translational model of MASLD-associated cardiac dysfunction that recapitulates the key features of human HFpEF. We applied functional and transcriptomic analyses of the left ventricle (LV) to define the pathways associated with cardiac dysfunction and its reversibility. MethodsAlms1-/- (Foz/Foz) mice and wild-type littermates were fed normal chow (NC) or Western diet (WD) for up to 36 weeks (wk). Reversibility was modeled by switching WD-fed Foz/Foz mice at 12wk back to NC for 12wk. Cardiac assessment included echocardiography, invasive hemodynamics with dobutamine stimulation, histopathology, electron microscopy and isolated cardiomyocyte contractility. LV transcriptomes were profiled by bulk RNA sequencing and analyzed by differential expression and pathway enrichment. ResultsFoz/Foz mice on WD for 24wk developed metabolic syndrome and MASH with advanced liver fibrosis. Cardiac phenotyping showed LV hypertrophy, impaired cardiomyocyte contractility, reduced {beta}-adrenergic reserve, elevated plasma BNP, and increased mortality while the ejection fraction was preserved (>50%), consistent with HFpEF. The progression of cardiac dysfunction was closely associated with liver fibrosis that developed during MASH. Switching WD-fed Foz/Foz mice at 12wk to normal chow diet reversed hepatic fibrosis, restored LV function, and reduced mortality, demonstrating plasticity of the liver-heart axis. LV transcriptomic analysis revealed that cardiac impairment in these mice was associated with mitochondrial dysfunction, altered substrate utilization, extracellular matrix remodeling, and metabolic stress; pathways that are similarly dysregulated in human HFpEF. Cardiac electron microscopy revealed swollen mitochondria with disrupted cristae, which improved following dietary intervention. ConclusionsMitochondrial dysfunction and fibroinflammatory remodeling are prominent features of MASLD-associated cardiac dysfunction. Reversal of hepatic and cardiac phenotypes with dietary intervention, together with elucidation of underlying pathways, establish the Foz/Foz model as a useful translational platform for studying liver-heart axis in MASLD. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/708088v2_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@60bd2aorg.highwire.dtl.DTLVardef@1234a09org.highwire.dtl.DTLVardef@1d1c5aborg.highwire.dtl.DTLVardef@1086089_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2025

Development of a floxed Gabbr2 gene allows for widespread conditional disruption of GABBR2 and recapitulates the phenotype of germline Gabbr2 knockout mice

GABBR1 and GABBR2 are widely expressed in the brain and genetic inhibition of their function leads to widespread neurologic dysfunction and premature death in mice. Given that GABBR1 and GABBR2 heterodimerize to form a functional receptor, global knockout of GABBR1 or GABBR2 results in a similar phenotype, characterized by spontaneous epileptiform activity, hyperlocomotor activity, hyperalgesia, impaired memory and premature death. It is now known that both GABBR1 and GABBR2 are expressed in a variety of tissues outside the nervous system and that GABA-B receptors can heterodimerize with other class C GPCRs, including the extracellular calcium-sensing receptor (CaSR). Studies in vitro have demonstrated that interactions with GABBR1 and GABBR2 can alter CaSR signaling in human embryonic kidney cells and breast cancer cells. The neurologic consequences of global loss of function of GABBR1 or GABBR2 has made it difficult to study the effects of loss of GABBR function in other organs. While a conditional knockout for GABBR1 is available, the GABBR2 gene had not been "floxed". We have used CRISPR to insert loxP sites into the GABBR2 locus in mice. These mice are normal at baseline but when bred with mice expressing Cre-recombinase under the control of the ubiquitously expressed Actin gene promoter, they recapitulate the phenotype of global GABBR2 knockout mice. Phenotypic changes through the brain, including the cortex, hippocampus and cerebellum. Evidence of abnormal neuronal function, increase cell death, and changes in neuronal architecture are seen throughout the brain of CRISPR knockout mice. These mice should be useful tools to study cell type-specific loss of GABBR2 function in the brain and other organs.

neuroscience↗

bioRxiv2019

AtDAT1 is a key enzyme of D-amino acid stimulated ethylene production in Arabidopsis thaliana

D-enantiomers of proteinogenic amino acids (D-AAs) are found ubiquitously, but the knowledge about their metabolism and functions in plants is scarce. A long forgotten phenomenon in this regard is the D-AA-stimulated ethylene production in plants. As a starting point to investigate this effect the Arabidopsis accession Landsberg erecta (Ler) got into focus as it was found defective in metabolizing D-AAs. Combining genetics and molecular biology of T-DNA lines and natural variants together with biochemical and physiological approaches we could identify AtDAT1 as a major D-AA transaminase in Arabidopsis. Atdat1 loss-of-function mutants and Arabidopsis accessions with defective AtDAT1 alleles were not able to produce D-Ala, D-Glu and L-Met, the metabolites of D-Met, anymore. This result corroborates the biochemical characterization of AtDAT1, which showed highest activity using D-Met as substrate. Germination of seedlings in light and dark led to enhanced growth inhibition of atdat1 mutants on D-Met. Ethylene measurements revealed an enhanced D-AA stimulated ethylene production in these mutants. According to initial working models of this phenomenon D-Met is preferentially malonylated instead of the ethylene precursor 1-aminocyclopropane-1-carboxylic acid (ACC). This decrease of ACC degradation should then lead to the increase of ethylene production. We could observe in our studies a reciprocal relation of malonylated methionine and ACC upon D-Met application and even significantly more malonyl-methionine in atdat1 mutants. Unexpectedly, the malonyl-ACC levels did not differ between mutants and wild type in these experiments. With AtDAT1, the first central enzyme of plant D-AA metabolism was characterized biochemically and physiologically. The specific effects of D-Met on ACC metabolization, ethylene production and plant development of dat1 mutants unraveled the impact of AtDAT1 on these processes, but they are not in full accordance to previous working models. Instead, our results imply the influence of additional candidate factors or processes on D-AA-stimulated ethylene production which await to be uncovered.

plant biology↗