FBS Colloquia No.424Ubiquitin Biology Laboratory
| Seminar or Lecture |
Excess Met1-ubiquitination leads to solid aggregate formation Minori Miyasaka [D2/D5, Ubiquitin Biology Laboratory] Mechanisms Underlying the Homeostatic Regulation of S-Adenosylmethionine Metabolism Soshiro Kashio [Assistant Professor, Ubiquitin Biology Laboratory] |
|---|---|
| Date and Time | 15 September 2026 (Tue), 12:15～13:00 |
| Place | 2F Seminar Room, BioSystems Building |
| Language | Japanese |
| Contact |
Kota Yanagitani (Associate Professor) |
Excess Met1-ubiquitination leads to solid aggregate formation
The ubiquitin ligase HOIL-1 regulates the formation of Met1-linked (linear) ubiquitin chains through its coordination with the E3 ligase HOIP within the Linear Ubiquitin Chain Assembly Complex (LUBAC). While HOIP-dependent Met1-linked ubiquitination is well established in inflammation and immunity, the physiological importance of its quantitative control remains unclear. Here, we show that cells expressing catalytically inactive HOIL-1 accumulate increased α-synuclein, tau, and amyloid-β aggregates. This is associated with defective late stage autophagic flux, characterized by impaired delivery of p62 positive aggregates to lysosomes. In parallel, p62 bodies undergo a biophysical transition from dynamic, liquid-like condensates to rigid, solid-like structures. Elevation of Met1-linked ubiquitin chains, either through HOIL-1 inactivation or depletion of the Met1-specific deubiquitinase OTULIN, phenocopies these defects. Together, our findings identify HOIL-1 as a key regulator of aggregate clearance and proteostasis through quantitative control of Met1-linked ubiquitination. （Preprint (BioRxiv): doi: https://doi.org/10.64898/2026.01.20.700516）
Mechanisms Underlying the Homeostatic Regulation of S-Adenosylmethionine Metabolism
Metabolism comprises the complex network of biochemical reactions that sustain life, and its homeostasis is essential for maintaining cellular and organismal functions. Recent advances in omics technologies have greatly expanded our understanding of metabolic pathways and metabolites that dynamically respond to environmental and physiological perturbations. In contrast, the mechanisms by which metabolic states are maintained despite such perturbations remain poorly understood. S-adenosylmethionine (SAM) is a central metabolite that serves as the universal methyl donor for the methylation of DNA, RNA, proteins, lipids, and many other biomolecules. However, despite fluctuations in nutrient availability and environmental conditions, the molecular mechanisms by which cells and organisms maintain SAM homeostasis remain largely unknown.
Using Drosophila melanogaster as a model organism, we have investigated the mechanisms that maintain SAM homeostasis under nutrient stress and aging. We previously found that reduced SAM biosynthetic capacity induces a decrease in the abundance of SAM-consuming enzymes, thereby preserving intracellular SAM levels. Furthermore, mechanistic analyses revealed that a cytoplasmic SAM-consuming enzyme is regulated by the nuclear ubiquitin–proteasome system, highlighting the importance of subcellular regulation in maintaining SAM metabolism. In this presentation, I will discuss the molecular basis and physiological significance of SAM homeostasis, with particular emphasis on mechanisms of SAM sensing and subcellular localization.
