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SUMO : glue or solvent for phase-separated ribonucleoprotein complexes and molecular condensates?
(2021)
Spatial organization of cellular processes in membranous or membrane-less organelles (MLOs, alias molecular condensates) is a key concept for compartmentalizing biochemical pathways. Prime examples of MLOs are the nucleolus, PML nuclear bodies, nuclear splicing speckles or cytosolic stress granules. They all represent distinct sub- cellular structures typically enriched in intrinsically disordered proteins and/or RNA and are formed in a process driven by liquid-liquid phase separation. Several MLOs are critically involved in proteostasis and their formation, disassembly and composition are highly sensitive to proteotoxic insults. Changes in the dynamics of MLOs are a major driver of cell dysfunction and disease. There is growing evidence that post-translational modifications are critically involved in controlling the dynamics and composition of MLOs and recent evidence supports an important role of the ubiquitin-like SUMO system in regulating both the assembly and disassembly of these structures. Here we will review our current understanding of SUMO function in MLO dynamics under both normal and pathological conditions.
Throughout their life cells of eukaryotic organisms can be confronted with a variety of proteotoxic stresses and in order to survive, corresponding resistance mechanisms had to evolve. Proteotoxic stresses can cause misfolding of proteins and accumulation of toxic protein aggregates. Failure to remove aggregates of misfolded proteins compromises cellular function and can ultimately cause cell death and disease. To deal with this challenge, cells utilize a complex network of protein quality control pathways, including chaperones, the ubiquitin-proteasome system and the autophagy system.
Another mechanism to cope with proteotoxic stresses is the stalling of translation initiation in order to save valuable resources and prevent faulty translation. Upon stress, intrinsically disordered RNA-binding proteins such as TIA-1 or G3BP1/2 are recruited to stalled preinitiation complexes and a network of multivalent interactions between RNAs and proteins is formed. These mRNP networks can merge with each other and phase separate into membraneless liquid-like structures called stress granules (SGs). Once stress is released, SGs are quickly resolved and translation continues. Yet, chronic stress or mutations of SG-associated proteins can cause persistent SGs, which can sequester misfolded proteins and have been linked to neurodegenerative diseases such as amyotrophic lateral sclerosis or frontotemporal dementia.
In mammalian cells, three isoforms of the small ubiquitin-related modifier (SUMO), SUMO1, SUMO2 and SUMO3 are covalently attached to lysine residues of target proteins. SUMO conjugation is catalyzed via an enzymatic cascade of an heteromeric E1 activating enzyme, the E2 conjugating enzyme Ubc9 and in some cases one of a limited number of E3 SUMO ligases. SUMOylation is a dynamic modification and can be reversed by SUMO isopeptidases, the best characterized of which belong to the SENP family. Cellular stresses such as heat or oxidative stress strongly induce SUMOylation resulting in increased numbers of poly-SUMOylation (formation of SUMO2/3 chains) on nuclear proteins.
The SUMO-targeted ubiquitin ligase (STUbL) RNF4 harbors four SUMO interaction motifs in its N-terminal domain. This feature allows RNF4 to specifically bind poly-SUMOylated proteins and catalyze their proteolytic or non-proteolytic ubiquitylation.
A variety of substrate proteins have been shown to undergo SUMO-primed ubiquitylation by RNF4 in response to stress or DNA damage. RNF4-mediated ubiquitylation is often a signal for proteolytic degradation of these substrates.
In this work we aimed by identify novel RNF4 targets, in heat-stressed cells in order to gain a wider understanding of the nuclear proteotoxic stress response. Analysis by mass spectrometry revealed that a large fraction of RNF4-interacting proteins in heatstressed cells are nuclear RNA-binding proteins, many of which shuttle outside the nucleus and associate with SGs upon stress. We validated, that nuclear RNA-binding proteins, such as TDP-43 and hnRNP M are indeed heat-induced targets of SUMOprimed ubiquitylation by RNF4.
These initial results led us to further investigate the links between the SUMO/RNF4-mediated, nuclear protein quality control and the dynamics of cytosolic heat- or arsenite-induced SGs. SUMO2/3 and RNF4 are mainly nuclear proteins and we confirmed that they do not associate with SGs. Yet, we could demonstrate that depletion of SUMO2/3, the E3 SUMO ligase PML or RNF4 as well as chemical inhibition of SUMOylation strongly delayed SG clearance upon stress release, indicating that a functional STUbL pathway is essential for the timely clearance of SGs.
Next, we investigated how stress-induced poly-SUMOylation is regulated. Our data shows that SENP levels and activities are reduced in response to heat and arsenite stress, which allows the buildup of poly-SUMO chains on nuclear proteins. Limitation of poly-SUMOylation by overexpression of the SUMO chain-specific isopeptidases SENP6 and SENP7 induced SG formation. In contrast, poly-SUMO-priming by chemical depletion of SENP6 with the drug hinokiflavone drastically limited SG formation upon stress treatment. These results indicate a clear role of chain-specific SENPs in the regulation of stress-induced poly-SUMOylation and SG dynamics.
Last, we investigated whether the STUbL pathway could affect the phase separation of FUSP525 (an ALS-linked mutant of the SG-associated protein FUS) and observed that perturbations of the STUbL pathway lead to an increased phase separation of FUSP525L.
Thus, our work connects the SUMO/RNF4 protein quality control mechanism to the dynamics of SGs supporting the hypothesis that release of proteotoxic stress in the nucleus facilitates the clearance of cytosolic SGs. Thereby, we discovered a previously unknown link between the nuclear and cytosolic axis of proteotoxic stress response.
Cortical tracking of stimulus features (such as the envelope) is a crucial tractable neural mechanism, allowing us to investigate how we process continuous music. We here tested whether cortical and behavioural tracking of beat, typically related to rhythm processing, are modulated by pitch predictability. In two experiments (n=20, n=52), participants’ ability to tap along to the beat of musical sequences was measured for tonal (high pitch predictability) and atonal (low pitch predictability) music. In Experiment 1, we additionally measured participants’ EEG and analysed cortical tracking of the acoustic envelope and of pitch surprisal (using IDyOM). In both experiments, finger-tapping performance was better in the tonal than the atonal condition, indicating a positive effect of pitch predictability on behavioural rhythm processing. Neural data revealed that the acoustic envelope was tracked stronger while listening to atonal than tonal music, potentially reflecting listeners’ violated pitch expectations. Our findings show that cortical envelope tracking, beyond reflecting musical rhythm processing, is modulated by pitch predictability (as well as musical expertise and enjoyment). Stronger cortical surprisal tracking was linked to overall worse envelope tracking, and worse finger-tapping performance for atonal music. Specifically, the low pitch predictability in atonal music seems to draw attentional resources resulting in a reduced ability to follow the rhythm behaviourally. Overall, cortical envelope and surprisal tracking were differentially related to behaviour in tonal and atonal music, likely reflecting differential processing under conditions of high and low predictability. Taken together, our results show diverse effects of pitch predictability on musical rhythm processing.
This book starts from the premise that the advent of mobile telephony in Mali coincided with economic liberalization, internationalization of trades and new balances in social spaces such as the Bamako market and the Center and Northern regions of Mali already under stress and / or major reconfigurations. These have resulted in increasing the mobility made ??both inside and outside the country (migrants and displaced persons, etc.); the appearance of new figures of businessmen, entrepreneurs, traders and changing trade routes. However, these mobilities produce original territories circulations and various exchanges that can not be understand in the exclusive setting of the local society. Perceived as pens or territorial ghettos, they are also anchors in cities. Centralities invisible and often confused with other businesses, these territories are also internalized operators forming networks between cities and the countryside. The investigated sites are representative of different scales: links, networks and territories across the Sahel and Sahara, and lastly of the territory enclosed within national boundaries, and finally across small parts of that territory, Douentza and the edges of the Sahara, the region of Kidal. In all cases it came to study in parallel, the social structure, the nature of territories or networks and actors that produce them, their links with urban areas, institutions, groups of actors embedded in these territories and movements registered by the use and ownership of the phone.
This article tries to outline possible research topics in the field of comparative 20th century legal history between Europe and Latin-America. It seeks to examine changes both in Labour and Property law as core areas where social conceptions began to influence »liberal« private law. Focussing on an example from Mexican law in the aftermath of the revolution which took place in the first decades of the 20th century, it is argued that new conceptions in both fields were discussed using similar conceptual patterns in Europe and LatinAmerica. In the reaction of the jurists from both continents to the challenges of the new century lies a possibility for fruitful comparison. Conducting research in such a framework can also produce comparative results on the interplay between constitutional law and private law – especially when the focus lies on Germany and Mexico, where new constitutions at the beginning of the new century did evoke reactions in the discourses about private law. With regard to methodology it has to be observed that such research has to go far beyond the traditional pattern of »reception« of legal concepts from Europe in Latin-America, and to highlight more complex ways of transition of legal forms between the two continents.
Raymond Saleilles (1855–1912) gilt als einer der größten Juristen seiner Epoche und Wegbereiter der französischen Rechtswissenschaft in ein neues Jahrhundert. Auch außerhalb Frankreichs hat sein vielschichtiges Werk in letzter Zeit historische Aufmerksamkeit erfahren, unter anderem mit Schwerpunkt auf der Rechtsvergleichung (Alfons Aragoneses) oder Saleilles’ Beurteilung der deutschen Rechtswissenschaft (Birte Gast). Der Florentiner Rechtshistoriker Marco Sabbioneti hat nun eine umfassende Monographie über Privatrechtsdogmatik und politisch-religiöse Grundeinstellungen des französischen Juristen vorgelegt, dessen Werk oft schlagwortartig mit – aus deutscher Sicht – kulturhistorischen Epocheneinteilungen wie "Belle Epoque" oder "Modernismo" in Verbindung gebracht wird. ...
In Germany, the termination of employment contracts is a central and often intensely debated legal issue today. This is not surprising since employment termination entails substantial risks for the person affected and threatens the very foundation of his or her economic existence. This is why both politics and legal dogmatics place the individual engaged in dependent work at the centre of concern as a subject requiring protection. In Germany, labour law ("Arbeitsrecht") emerged as an independent field of law focusing on the persona of the dependent worker ("Arbeitnehmer") and its typified normative ascriptions. This process took place in the course of the 20th century, as the concept of the principal requirement that employees be protected against unforeseen or unjustified dismissal became increasingly established, giving rise to very intricate regulations. Social security is a guiding motif of this legislation which regards contract termination primarily as a risk. It is often not considered that this constellation is a very new one. Defined conceptions of the interests of the parties to labour contracts also existed before 1900, but social security was then not a central criterion. At that time, many people perceived the termination of their employment as an opportunity rather than primarily as a risk. Employers, on the other hand, aimed to keep people in their service for as long as possible. In the late 19th century, the enforcement of labour performance by legal means and normative instruments, which no longer plays any role today, was still an important issue. This provides occasion to investigate the freedom of working people from the perspective of the history of law, whereby this article focuses on the history of the German-speaking territories. ...
Die Geschichte klingt bekannt: Ein Rechtssystem etabliert im 19. Jahrhundert eine liberale institutionelle Ordnung. Eine Verfassung garantiert mehr oder weniger verbindlich individuelle Rechte, flankiert von einer prinzipiell nach Vertragsfreiheit und Eigentumsfreiheit gestalteten Privatrechtskodifikation. Zu Beginn des 20. Jahrhunderts gerät das liberale Gleichgewicht jedoch ins Wanken. Arbeitende Menschen artikulieren ihre Interessen schärfer als zuvor, es entsteht revolutionärer Sprengstoff, die "soziale Frage" ist allgegenwärtig und das Privatrecht der alten Ordnung scheint keine Antworten darauf zu haben. Es beginnt ein Ringen zwischen neuen, zunehmend radikalen politischen Bekenntnissen, die den Gegensatz der Klassen entweder zugunsten einer Klasse – wenn nötig gewaltsam – entscheiden oder ihn beseitigen wollen, durch Harmonisierung widerstreitender Interessen. Die neuen politischen Richtungen beeinflussen entscheidend das Privatrecht. Das Arbeitsrecht, als neu entstehende Disziplin, gerät in das Spannungsfeld der politischen Glaubenskämpfe des neuen Jahrhunderts und gewinnt gerade durch sie an Relevanz. ...
In der Präambel des europäischen Verfassungsvertrags von 2004 war das neu zu ordnende politische Gemeinwesen als ein "nach schmerzlichen Erfahrungen nunmehr geeintes Europa" beschrieben worden, das sich gerade wegen dieser Erfahrungen auf einen Weg des Fortschritts und der Zivilisation begeben habe. Dem normativen Text hatte man also einen offiziellen Hinweis auf Europas Geschichte vorangestellt. Die Union sollte nicht mehr in erster Linie als nüchterner ökonomischer Zweckverband präsentiert werden, sondern als notwendiges Ergebnis historischer Erfahrung, als universellen Werten zustrebende, rechtsstaatlich verfasste Schicksalsgemeinschaft von Menschen, die sich ihrer gemeinsamen Wurzeln und Ziele bewusst sind. Auch wenn das ehrgeizige Projekt einer europäischen Verfassung inzwischen gescheitert, die Union wieder auf dem Boden der konferenzdiplomatischen Tatsachen gelandet und zur üblichen, zähen Verhandlungsroutine zurückgekehrt ist, bleibt die Rolle der Vergangenheit im europäischen Einigungsprozess ein kompliziertes wie faszinierendes Thema. ...