Leskova, A. | Search bioRxiv

bioRxiv2026

NRAMP2 controls manganese partitioning between seed coat and embryo to regulate seed vigor

Seed development and germination depend on the coordinated transport of macronutrients and micronutrients, which sustain the embryo and determine seed vigour. Manganese (Mn) is an essential micronutrient involved in various metabolic processes, yet its role in seed development is not well understood. In this study, we investigated manganese (Mn) homeostasis in seeds and identified NRAMP2, a previously characterised trans-Golgi-localised Mn exporter, as a key transporter that controls Mn delivery to the embryo. Promoter analysis showed NRAMP2 expression in the chalazal region, which is a central hub for the exchange of nutrients between maternal tissues and the developing seed. X-ray fluorescence mapping revealed mislocalisation of Mn in nramp2 mutant seeds, retention of Mn on the seed coat and markedly reduced levels of Mn in the embryo. Functionally, Mn depletion delayed seed germination and increased physiological dormancy by reducing reactive oxygen species (ROS) accumulation. Our results uncover the vital role of Mn in supporting embryo development and seed vigour, establishing NRAMP2 as a pivotal component of the Mn transport machinery during seed development.

plant biology↗

bioRxiv2025

Translational control of AMPK activity in melanoma

The eIF4F translation initiation complex controls ERK MAPK signaling in malignant melanomas with BRAF and NRAS mutations. It also contributes to the development of melanoma resistance to therapies targeting BRAF and MEK kinases. Here, we uncovered a critical role for eIF4F in regulating the main cellular metabolic sensor, AMP-activated protein kinase (AMPK). In melanoma cells with the most common BRAF V600E mutation, ERK and AMPK pathway activities were reported as mutually exclusive. This is because BRAF-driven ERK activity negatively impacts LKB1-mediated canonical AMPK activation. However, we observed that eIF4F inhibition can stimulate AMPK activity in melanoma cells, both in vitro and in vivo, despite concomitant ERK hyperactivation. Notably, the protein levels of LKB1 and its co-factor MO25 were sensitive to eIF4F inhibition, indicating a non-canonical LKB1-independent mechanism of AMPK activation. In a proteomic screen, we aimed to identify eIF4F roles in melanoma cell physiology beyond the MAPK pathway. We found that the eIF4F function is essential for maintaining cellular levels of key cell cycle and metabolic regulators, including CDK1, CDK2, TYMS, and UHRF1. Importantly, we also identified the protein phosphatase PP2A as a new eIF4F target. Our subsequent analyses showed that inhibition or siRNA-mediated knockdown of PP2A increases AMPK activity in melanoma cells, independent of LKB1. This data shows that PP2A plays a significant role in regulating AMPK activity in melanoma. Thus, eIF4F inhibition not only impairs canonical AMPK activators but also downregulates PP2A, which negatively regulates AMPK dynamics. Collectively, our data highlight a dual role of eIF4F in the control of AMPK in BRAF-mutant melanoma cells. It maintains the canonical AMPK signaling pathway while simultaneously limiting the extent of AMPK activation via the eIF4F-PP2A-AMPK axis. Pharmacological inhibition of this axis can overcome the negative control of AMPK signaling by the ERK pathway. This suggests new therapeutic opportunities to disrupt melanoma growth.

cancer biology↗