Biology subjects

Komatsu, M.

Publications and source records attributed to Komatsu, M..

22 records · Page 2Linked to original sources

bioRxiv2019

Autophagy controls lipid droplet formation by fine-tuning NCoR1 levels

Lipid droplets (LDs) are dynamic organelles that store neutral lipids during times of energy excess, such as following a meal. LDs serve as an energy reservoir during fasting and have a buffering capacity that prevents lipotoxicity. Autophagy and the autophagic machinery have been proposed to play a role in LD biogenesis but the underlying molecular mechanism remains unclear. Here, we show that when nuclear receptor co-repressor 1 (NCoR1), which inhibits the transactivation of nuclear receptors, accumulates due to autophagy suppression, LD biogenesis is blocked. Ablation of ATG7, a gene essential for autophagy, suppressed the expression of gene targets of liver X receptor (LXR), a nuclear receptor responsible for fatty acid and triglyceride synthesis in an NCoR1-dependent manner. LD biogenesis in response to fasting and after hepatectomy was hampered by the suppression of autophagy. These results indicate that autophagy controls physiological hepatosteatosis by fine-tuning NCoR1 protein levels.

cell biology↗

bioRxiv2019

NBR1-mediated p62-liquid droplets enhance the Keap1-Nrf2 system

p62/SQSTM1 is a multivalent protein that has an ability to cause a liquid-liquid phase separation and serves as a receptor protein that participates in cargo isolation during selective autophagy. This protein is also involved in the non-canonical activation of the Keap1-Nrf2 system, a major oxidative stress response pathway. Here we show a role of Neighbor of BRCA1 gene 1 (NBR1), an autophagy receptor structurally similar to p62/SQSTM1, in the p62-liquid droplet formation and the Keap1-Nrf2 pathway. The overexpression of NBR1 blocked selective degradation of p62/SQSTM1 through autophagy and promoted the accumulation and phosphorylation of p62/SQSTM1 in liquid-like bodies, which is required for the activation of Nrf2. NBR1 was induced in response to oxidative stress, and then the p62-mediated Nrf2 activation was up-regulated. Conversely, loss of Nbr1 suppresses not only the formation of p62/SQSTM1-liquid droplets but also p62-dependent Nrf2 activation during oxidative stress. Taken together, our results show that NBR1 mediates p62/SQSTM1-liquid droplet formation to activate the Keap1-Nrf2 pathway.

cell biology↗

bioRxiv2019

Exosome-mediated MIR211 modulates tumor microenvironment via the DUSP6-ERK5 axis and contributes to BRAFV600E inhibitor resistance in melanoma.

The microRNA MIR211 is an important regulator of melanoma tumor cell behavior. Previous studies suggested that in certain tumors, MIR211 acted as a tumor suppressor while in others it behaved as an oncogenic regulator. When MIR211 is expressed in BRAFV600E-mutant A375 melanoma cells in mouse xenografts, it promotes aggressive tumor growth accompanied by increased cellular proliferation and angiogenesis. We demonstrate that MIR211 is transferred to adjacent cells in the tumor micro-environment via exosomes. Cross-species genome-wide transcriptomic analysis showed that human tumor-derived MIR211 interacts with the mouse transcriptome in the tumor microenvironment, and activates ERK5 signaling in human tumor cells via the modulation of a feedback loop. Human miR211 directly inhibits human DUSP6 protein phosphatase at the post-transcriptional level. We provide support for the hypothesis that DUSP6 inhibition conferred resistance of the human tumor cells to the BRAF inhibitor vemurafenib and to the MEK inhibitor cobimetinib, with associated increases in ERK5 phosphorylation. These findings are consistent with a model in which MIR211 regulates melanoma tumor proliferation and BRAF inhibitor resistance by inducing ERK5 signaling within the complex tumor microenvironment. We propose that the MIR211-ERK5 axis represents an important and sensitive regulatory arm in melanoma with potential theranostic applications.

cancer biology↗

bioRxiv2018

EECoG-Comp: An Open Source Platform for Concurrent EEG/ECoG Comparisons

Electrophysiological Source Imaging (ESI) methods are hampered by the lack of "gold standards" for model comparison. Concurrent electroencephalography (EEG) and electrocorticography (ECoG) recordings (namely EECoG) are considered gold standard to validating EEG generative models with primate models have the unique advantages of both flexibility and translational value in human research. However the severe EEG artifacts during such invasive experiments, the complexity of providing sufficiently detailed biophysical models, as well as lacking sound statistical connectivity comparison methods have hampered the availability and analysis of such datasets. In this paper, 1) we provide EECoG-Comp: an open source platform (https://github.com/Vincent-wq/EECoG-Comp) which encompasses the preprocessing, forward modeling, simulation and comparison module; 2) we take the simultaneous EECoG dataset from www.neurotycho.org as an example to illustrate the use of this platform and compare the source connectivity estimation performance of 4 popular ESI methods named MNE, LCMV, eLORETA and SSBL. The conclusion shows the limits of performance of these ESI connectivity estimators using both simulations and real data analysis. In fact, the use of this platform also suggests the need for both improved simultaneous EEG and ECoG experiments and ESI connectivity estimators.

bioinformatics↗