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Michler, T.

Publications and source records attributed to Michler, T..

2 recordsLinked to original sources

An ancient cis-element regulates translation of arginine decarboxylase to control downstream polyamine biosynthesis and stress responses

Polyamines (PAs) are ubiquitous metabolites that, despite their simple structure, profoundly influence plant growth, development, and stress adaptation. Their cellular levels are largely determined by arginine decarboxylase (ADC), a key rate-limiting enzyme in their biosynthesis. We previously identified a [~]50 bp GC-rich sequence in the 5' untranslated region (UTR) of plant ADC genes, termed the ADC-box, that is conserved across land plants. Transient reporter assays in tomato, in which ADC upstream regions were decoupled from their native coding sequences and fused to reporter genes, suggested that this element represses translation. However, its function in the native genomic context and its impact on PA homeostasis remain unclear. Here, we combined CRISPR-Cas9 genome editing, metabolite profiling, enzymatic assays, and RNA structure probing to define ADC-box function in tomato and in the seedless land plant Marchantia polymorpha, which retains a conserved [~]20 bp core region. Mutation of the M. polymorpha ADC-box increased ADC activity and altered PA levels, indicating that the ADC-box functions as a conserved translational repressor. In tomato, disruption of the ADC-boxes in SlADC1 and SlADC2 increased ADC activity, demonstrating that the ADC-box acts as a translational repressor in its native context. These ehects were most pronounced under cold stress, when ADC transcript levels increase, suggesting that the ADC-box buhers stress-induced translation. Metabolically, ADC-box disruption led to agmatine accumulation and alterations in upstream intermediates, while downstream PA pools remained largely unchanged. SHAPE analysis revealed that the tomato ADC-box folds into a three-stem RNA structure, with a central stem representing the major inhibitory module. ADC-box mutants displayed altered plant-microbe interactions, with enhanced resistance to Pseudomonas syringae and Tobacco rattle virus, but increased susceptibility to Ralstonia solanacearum and Tomato yellow leaf curl virus. Together, these findings establish the ADC-box as an evolutionarily conserved cis-regulatory element that stabilizes PA homeostasis and modulates plant-microbe interactions.

plant biology↗

Hypoxic gene expression in chronic hepatitis B infected patients is not observed in state-of-art in vitro and mouse infection models

Hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC) worldwide. The prolyl hydroxylase domain (PHD)-hypoxia inducible factor (HIF) pathway is a key mammalian oxygen sensing pathway and is frequently perturbed by pathological states including infection and inflammation. We discovered a significant upregulation of hypoxia regulated gene transcripts in patients with chronic hepatitis B (CHB) in the absence of liver cirrhosis. We used state-of-the-art in vitro and in vivo HBV infection models to evaluate a role for HBV infection and the viral regulatory protein HBx to drive HIF-signalling. HBx had no significant impact on HIF expression or associated transcriptional activity under normoxic or hypoxic conditions. Furthermore, we found no evidence of hypoxia gene expression in HBV de novo infection, HBV infected human liver chimeric mice or transgenic mice with integrated HBV genome. Collectively, our data show clear evidence of hypoxia gene induction in CHB that is not recapitulated in existing models for acute HBV infection, suggesting a role for inflammatory mediators in promoting hypoxia gene expression.

microbiology↗