Biology subjects

van Leeuwen, W.

Publications and source records attributed to van Leeuwen, W..

3 recordsLinked to original sources

bioRxiv2022

Stress-induced phase separation of ERES components into Sec bodies precedes ER exit inhibition in mammalian cells.

Phase separation of ER-exit-sites (ERES) components into membraneless compartments, the Sec bodies, occurs in Drosophila cells upon specific cellular stressors, i.e., salt stress and amino acid starvation, and their formation is linked to the inhibition of the early secretory pathway. Here, we show Sec bodies also form in secretory mammalian INS-1 cells upon the same stress. These reversible and membraneless structures are positive for ERES components, including both isoforms of Sec16 (A and B) and COPII subunits. We find that Sec16A, but not Sec16B, is a driver for Sec body formation. We show that the coalescence of ERES components into Sec bodies occurs by fusion, in line with their liquid-droplet properties. Lastly, we demonstrate that stress-induced ER-exit inhibition is a consequence of the significant coalescence of Sec16A into Sec bodies, leading to its depletion from ERES that become non-functional. Stress relief causes an immediate dissolution of Sec bodies and the concomitant restoration of protein exit from the ER. We propose a model in which dynamic conversion between ERES and Sec body assembly, driven by Sec16A, regulates protein exit from the ER during stress and upon stress relief in mammalian cells, thus providing a conserved pro-survival mechanism in response to stress.

cell biology↗

bioRxiv2021

Salt Inducible Kinase activation and IRE1-dependent intracellular ATP depletion to form Sec bodies in Drosophila cells.

The phase separation of the non-membrane bound Sec bodies occurs in Drosophila S2 cells by coalescence of components of the ER exit sites under the stress of amino-acid starvation. Here we address which signaling pathways cause Sec body formation. We find that two pathways are critical. The first is a SIK dependent pathway induced by salt (NaCl) stress in a necessary and sufficient manner. The second is the activation of IRE1 (one of the key kinases mediating the Unfolded Protein Response) by absence of amino- acids, which partly leads to the depletion of intracellular ATP. However, IRE1 activation is not sufficient to induce Sec body formation and needs to be combined to salt stress. This works pioneers the role of SIK in phase transition and re-enforces the role of IRE1 as a metabolic sensor for the level of circulating amino-acids.

cell biology↗

bioRxiv2019

The effect of acute stress on the balance between goal-directed and habit networks in obsessive-compulsive disorder.

The classical cognitive-behavioral theory of obsessive-compulsive disorder (OCD) holds that compulsions are performed to reduce distress that is evoked by obsessions, whereas a recent neuroscience-inspired theory suggests that compulsivity results from a disbalance between goal-directed and habit-related neural networks. To bridge these theories, we investigated whether the balance between goal-directed and habit networks in patients with OCD was affected in the late aftermath of stress. Twenty-three OCD patients and twenty-three healthy controls participated in a controlled stress induction paradigm using the socially evaluated cold-pressor test in a crossover design. Stress responses were evaluated through cortisol levels, blood pressure, and anxiety ratings. Functional connectivity of the caudate nucleus and posterior putamen was assessed using seed region analysis of resting-state functional magnetic resonance imaging data, which are hubs of the goal-directed and habit network, respectively. Stress induction increased blood pressure and psychological stress measures across groups and resulted in blunted cortisol responses in patients. Furthermore, patients showed a blunted reduction in connectivity between the caudate nucleus and precuneus in the aftermath of stress, which was positively correlated with compulsivity but not obsession severity. The posterior putamen showed no significant group differences in stress-induced connectivity. These results suggest that compulsivity in OCD in the aftermath of stress is associated with altered connectivity between the goal-directed and default mode networks.

neuroscience↗