Biology subjects

Myers, N.

Publications and source records attributed to Myers, N..

3 recordsLinked to original sources

bioRxiv2018

Temporally unconstrained decoding reveals consistent but time-varying stages of stimulus processing

In this paper, we propose a method to track trial-specific neural dynamics of stimulus processing and decision making with high temporal precision. By applying this novel method to a perceptual template-matching task, we tracked representational brain states associated with the cascade of neural processing, from early sensory areas to higher-order areas that are involved in integration and decision-making. We address a major limitation of the traditional decoding approach: that it relies on consistent timing of these processes over trials. Using a temporally unconstrained decoding analysis approach, we found that the timing of the cognitive processes involved in perceptual judgements can vary considerably over trials. This revealed that the sequence of processing states was consistent for all subjects and trials, even when the timing of these states varied. Furthermore, we found that the specific timing of states on each trial was related to the quality of performance over trials.

neuroscience↗

bioRxiv2017

Oncogenic addiction to high 26S proteasome levels

Proteasomes are large intracellular complexes responsible for the degradation of cellular proteins. The altered protein homeostasis of cancer cells results in increased dependency on proteasome function. There are several different proteasome complexes that may be assembled in cells, with the 20S catalytic core common to them all. 20S proteasomes can function in isolation, or as part of larger complexes (26S) with regulatory particles (RP) such as the 19S that is needed for the targeting and processing of ubiquitinated substrates. Proteasome inhibitors target the catalytic barrel (20S) and thus this inhibition does not allow the deconvolution of the distinct roles of 20S vs. 26S proteasomes in cancer progression. We examined the degree of dependency of cancer cells specifically to the level of the 26S proteasome complex. We found that oncogenic transformation of human and mouse immortalized cells with mutant Ras induced a strong increase in the translation of the 26S proteasome subunits, giving rise to high 26S complex levels. We show that depletion of a single subunit of the 19S RP was sufficient to significantly reduce the 26S proteasome level and lower the cellular 26S/20S ratio. We further demonstrate that the accumulated 26S proteasome was essential for the viability of the transformed cells. Moreover, the viability of 20 different cancer cell lines, but not normal human fibroblasts, was severely compromised upon specific 26S proteasome suppression regardless of their p53 status. Suppression of 26S activated the UPR and Caspase-3, which at least partially explains the cell-killing effect. Morphologically, suppression of the 26S proteasome resulted in cytoplasm shrinkage and nuclear deformation. Thus, the tumor cell-specific addiction to high 26S proteasome levels sets the stage for future strategies in cancer therapy.

cancer biology↗

bioRxiv2017

A 20S proteasome receptor for degradation of intrinsically disordered proteins

Degradation of intrinsically disordered proteins (IDPs) by the 20S proteasome, unlike ubiquitin-dependent 26S proteasomal degradation, does not require proteasomal targeting by polyubiquitin. However, how these proteins are recognized by the proteasome was unknown. We report here on a mechanism of 20S proteasome targeting. Analysis of protein interactome datasets revealed that the proteasome subunit PSMA3 interacts with many IDPs. By employing in vivo and cell-free experiments we demonstrated that the PSMA3 C-terminus binds p21, c-Fos and p53, all IDPs and 20S proteasome substrates. A 69 amino-acids long fragment is autonomously functional in interacting with IDP substrates. Remarkably, this fragment in isolation blocks the degradation of a large number of IDPs in vitro and increases the half-life of proteins in vivo. We propose a model whereby the PSMA3 C-terminal region plays a role of substrate receptor in the process of proteasomal degradation of many IDPs.

molecular biology↗