The ETI-dependent receptor-like kinase 1 positively regulates effector-triggered immunity by stabilizing NLR-required for cell death 4 in Nicotiana benthamiana.

Leucine-rich repeat receptor-like kinases (LRR-RLKs) comprise the largest class of membrane-localized receptor-like kinases in plants. Leucine-rich repeat receptor-like kinases are key immune sectors contributing to pattern-triggered immunity (PTI), but whether LRR-RLK mediates effector-triggered immunity (ETI) in plants remains unclear. In this study, we evaluated the function of LRR-RLKs in regulating ETI by using a virus-induced gene silencing (VIGS)-based reverse genetic screening assay, and identified a LRR-RLK named ETI-dependent receptor-like kinase 1 (EDK1) required for ETI triggered by the avirulence effector AVRblb2 secreted by Phytophthora infestans and its cognate receptor Rpi-blb2. Silencing or knockout of EDK1 compromised immunity mediated by Rpi-blb2 and the cell death triggered by recognition of AVRblb2. NLR-required for cell death 4 (NRC4), a signaling component acts downstream of Rpi-blb2, was identified that interacts with EDK1 using the LC-MS analysis and the interaction was further evaluated by co-immunoprecipitation. EDK1 promotes protein accumulation of NRC4 in a kinase-dependent manner and positively regulates resistance to P. infestans in Nicotiana benthamiana. Our study revealed that EDK1 positively regulates plant ETI through modulating accumulation of the NLR signaling component NRC4, representing a new regulatory role of the membrane-localized LRR-RLKs in plant immunity.

A novel basement membrane-related gene signature predicts prognosis and immunotherapy response in hepatocellular carcinoma.

Background: Basement membranes (BMs) have recently emerged as significant players in cancer progression and metastasis, rendering them promising targets for potential anti-cancer therapies. Here, we aimed to develop a novel signature of basement membrane-related genes (BMRGs) for the prediction of clinical prognosis and tumor microenvironment in hepatocellular carcinoma (HCC). Methods: The differentially expressed BMRGs were subjected to univariate Cox regression analysis to identify BMRGs with prognostic significance. A six-BMRGs risk score model was constructed using Least Absolute Shrinkage Selection Operator (LASSO) Cox regression. Furthermore, a nomogram incorporating the BMRGs score and other clinicopathological features was developed for accurate prediction of survival rate in patients with HCC. Results: A total of 121 differentially expressed BMRGs were screened from the TCGA HCC cohort. The functions of these BMRGs were significantly enriched in the extracellular matrix structure and signal transduction. The six-BMRGs risk score, comprising CD151, CTSA, MMP1, ROBO3, ADAMTS5 and MEP1A, was established for the prediction of clinical prognosis, tumor microenvironment characteristics, and immunotherapy response in HCC. Kaplan-Meier analysis revealed that the BMRGs score-high group showed a significantly shorter overall survival than BMRGs score-low group. A nomogram showed that the BMRGs score could be used as a new effective clinical predictor and can be combined with other clinical variables to improve the prognosis of patients with HCC. Furthermore, the high BMRGs score subgroup exhibited an immunosuppressive state characterized by infiltration of macrophages and T-regulatory cells, elevated tumor immune dysfunction and exclusion (TIDE) score, as well as enhanced expression of immune checkpoints including PD-1, PD-L1, CTLA4, PD-L2, HAVCR2, and TIGIT. Finally, a multi-step analysis was conducted to identify two pivotal hub genes, PKM and ITGA3, in the high-scoring group of BMRGs, which exhibited significant associations with an unfavorable prognosis in HCC. Conclusion: Our study suggests that the BMRGs score can serve as a robust biomarker for predicting clinical outcomes and evaluating the tumor microenvironment in patients with HCC, thereby facilitating more effective clinical implementation of immunotherapy.