Baptiste, G. | bioRxiv Science

bioRxiv2021

Both transient and sustained MPK3/6 activities positively control expression of NLR genes in PTI and ETI.

Arabidopsis thaliana Mitogen Activated Protein Kinases 3 and 6 (MPK3/6) are known to be activated transiently in PAMP-Triggered Immunity (PTI) and durably in Effector-Triggered Immunity (ETI). However the functional differences between these two kinds of activation kinetics and how they allow coordination of the two layers of plant immunity remain poorly understood. Here, by analysing suppressors of the phenotype caused by a constitutively active form of MPK3, we demonstrate that ETI-mediating nucleotide-binding domain leucine-rich repeat receptors (NLRs) and NLR signaling can act downstream of MPK3 activities. Moreover we provide evidence that both sustained and transient MPK3/6 activities positively control the expression of at least two NLR genes, AT3G04220 and AT4G1110. We further show that the ETI regulators NDR1 and EDS1 also contribute to the upregulations of these two NLRs not only in an ETI context but also in a PTI context. Remarkably, while in ETI, MPK3/6 activities are dependent on NDR1 and EDS1, they are not in PTI, suggesting that if the same actors are involved in the two layers of immunity, the way they are interconnected is different. Finally we demonstrate that expression of the NLR AT3G04220 is sufficient to induce expression of defense genes from the SA branch. Overall this study enlarges our knowledge of MPK3/6 functions during immunity and gives a new insight into the intrication of PTI and ETI.

plant biology↗

bioRxiv2021

Integrated Systems-Analysis of the Human and Murine Pancreatic Cancer Glycomes Reveal a Tumor Promoting Role for ST6GAL1

Pancreatic ductal adenocarcinoma (PDA) is the 3rd leading cause of cancer-death in the U.S.. Glycans, such as CA-19-9, are biomarkers of PDA and are emerging as important modulators of cancer phenotypes. Herein, we utilized a systems-based approach integrating glycomic analysis of human PDA and the well-established KC mouse model, with transcriptomic data to identify and probe the functional significance of aberrant glycosylation in pancreatic cancer. We observed both common and distinct patterns of glycosylation in pancreatic cancer across species. Common alterations included increased levels of -2,3- and -2,6-sialic acids, bisecting GlcNAc and poly-LacNAc. However, core fucose, which was increased in human PDAC, was not seen in the mouse, indicating that not all human glycomic changes can be modeled in the KC mouse. In silico a nalysis of bulk and single cell sequencing data identified ST6GAL1, which underlies -2,6-sialic acid, as overexpressed in human PDA, concordant with histological data. Enzymes levels correlated with the stage of clinical disease. To test whether ST6GAL1 promotes pancreatic cancer we created a novel mouse in which a pancreas-specific genetic deletion of this enzyme overlays the KC mouse model. Analysis of our new model showed delayed cancer formation and a significant reduction in fibrosis. Our results highlight the importance of a strategic systems-approach to identifying glycans whose functions can be modeled in mouse, a crucial step in the development of therapeutics targeting glycosylation in pancreatic cancer. SIGNIFICANCEPancreatic ductal adenocarcinoma (PDA) is the 3rd leading cause of cancer-death in the U.S.. Glycosylation is emerging as an important modulator of cancer phenotype. Herein we use a systems-approach integrating glycomics of human PDA and a well-established PDA mouse model with transcriptomic data to identify ST6GAL1, the enzyme underlying -2,6-sialic acid, as a potential cancer promoter. A pancreatic specific ST6GAL1 knockout in the KC mouse showed delayed cancer formation and a reduction in fibrosis. Our results highlight the importance of a strategic systems-approach to identifying glycans whose functions can be modeled in mouse, a crucial step in the development of therapeutics targeting glycosylation in pancreatic cancer.

cancer biology↗