The nucleolus is a prominent subnuclear compartment, where ribosome biosynthesis takes place. Recently, the nucleolus has gained attention for its novel role in the regulation of cellular stress. Nucleolar stress is emerging as a new concept, which is characterized by diverse cellular insult-induced abnormalities in nucleolar structure and function, ultimately leading to activation of p53 or other stress signaling pathways and alterations in cell behavior. Despite a number of comprehensive reviews on this concept, straightforward and clear-cut way criteria for a nucleolar stress state, regarding the factors that elicit this state, the morphological and functional alterations as well as the rationale for p53 activation are still missing. Based on literature of the past two decades, we herein summarize the evolution of the concept and provide hallmarks of nucleolar stress. Along with updated information and thorough discussion of existing confusions in the field, we pay particular attention to the current understanding of the sensing mechanisms, i.e., how stress is integrated by p53. In addition, we propose our own emphasis regarding the role of nucleolar protein NPM1 in the hallmarks of nucleolar stress and sensing mechanisms. Finally, the links of nucleolar stress to human diseases are briefly and selectively introduced.

The rule of one terminal and one transmitter acting on one synapse clearly fails to cover the complexity of chemical synapse operation in the brain. Compelling evidence now indicates that two transmitters can be released from the same terminal, acting in a complementary manner to generate complex electrical activity in the targets. Our laboratory now showed that a subpopulation striatal cholinergic neurons also release the classical inhibitory transmitter GABA with a balance between excitation and inhibition being provided by acetylcholine and GABA, respectively. An illustration of the importance of this dual release comes from the fact that when dopamine signals are absent such as in Parkinson disease (PD) the GABAergic inhibition in these dual cholinergic/GABAergic cells fails because of high intracellular chloride ((Cl^–)_I) levels rendering the cholinergic excitatory component unmet by a parallel inhibitory drive. Restoring low (Cl^–)_I with the NKCC1 chloride importer antagonist bumetanide attenuates the electrical and motor disturbance. In addition to illustrating the complex interactions between two transmitters acting at the same synapse, this study paves the way to novel conceptual treatment of PD based on restoration of GABAergic inhibition in keeping with our pilot clinical trial showing indeed that bumetanide together with levodopa attenuates axial motor disturbance. It is also in keeping with extensive investigations showing increased (Cl^–)_I levels and weakened inhibition in a wide range of pathological insults and their restoration by bumetanide. It raises fundamental issues related to the operation of the striatum and basal ganglia in health and disease.

Type 1 diabetes mellitus (T1DM) is defined as an autoimmune disease that targets the selective destruction of islet insulin-producing beta cells by infiltrating immune cells (insulitis). As a result, the organism is no longer able to produce insulin and develops hyperglycaemia and, if untreated, death. Despite advances in medical device technology and insulin analogues as well as strives in generating in vitro insulin-producing cells, there is still no robust therapy to substitute and protect beta cells that are lost in T1DM. Clinical trials aimed at blocking the immune-mediated beta cell destruction have had moderate success leaving a gap in our understanding of disease aetiology. Such breach in knowledge may stem from the oversight that inhibiting the immune attack likely impairs beta cell regeneration and emphasizes a fundamental paradigm in the approach to treat the disease: A non-mutually exclusive strategy in which the uncontrolled self-directed inflammatory immune response (and not the global immune system) as well as beta cell regeneration are exquisitely fine tuned in order to successfully regain immunological tolerance and restoration of a functional beta cell mass. As such, defining factors that can guide a pro-inflammatory immune cell destructive environment towards an anti-inflammatory environment facilitating beta cell survival and stimulate regeneration would define an unprecedented class of immune-regenerative therapeutic agents for T1DM. In our recent study we identify the liver receptor homolog 1 (LRH-1, also known as NR5A2) as a ‘druggable’ target that fulfills these criteria restoring glycemic control in various mouse models of T1DM as well as improving human islet survival and function both in vitro and in vivo (Nat Comms, 9:1488).

Activation of the NLRC4 inflammasome is crucial for defense against bacterial species that have flagellin or the type III secretion system (T3SS). We have discovered the role of interferon regulatory factor 8 (IRF8) in mediating NLRC4 inflammasome activation. IRF8 is required for the transcription of genes encoding NAIPs, thereby enabling cellular detection of flagellin or T3SS proteins. In vivo, IRF8 is important for NLRC4 inflammasome–dependent cytokine production, bacterial clearance, and ultimately, host survival. By introducing IRF8 as a player in inflammasome regulation, our study provides a new perspective on that process.