The autoinflammation-associated NLRC4 mutation increases microbiota-independent IL-18 production but does not recapitulate human autoinflammatory symptoms in mice.

Background: Autoinflammation with infantile enterocolitis (AIFEC) is an often fatal disease caused by gain-of-function mutations in the NLRC4 inflammasome. This inflammasomopathy is characterized by macrophage activation syndrome (MAS)-like episodes as well as neonatal-onset enterocolitis. Although elevated IL-18 levels were suggested to take part in driving AIFEC pathology, the triggers for IL-18 production and its ensuing pathogenic effects in these patients are incompletely understood.

Myeloid OTULIN deficiency couples RIPK3-dependent cell death to Nlrp3 inflammasome activation and IL-1β secretion.

Loss-of-function mutations in the deubiquitinase OTULIN result in an inflammatory pathology termed "OTULIN-related autoinflammatory syndrome" (ORAS). Genetic mouse models revealed essential roles for OTULIN in inflammatory and cell death signaling, but the mechanisms by which OTULIN deficiency connects cell death to inflammation remain unclear. Here, we identify OTULIN deficiency as a cellular condition that licenses RIPK3-mediated cell death in murine macrophages, leading to Nlrp3 inflammasome activation and subsequent IL-1β secretion.

Blood-based test for diagnosis and functional subtyping of familial Mediterranean fever.

Background And Objective: Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease (AID) worldwide. The disease is caused by mutations in the gene encoding the inflammasome sensor Pyrin. Clinical diagnosis of FMF is complicated by overlap in symptoms with other diseases, and interpretation of genetic testing is confounded by the lack of a clear genotype-phenotype association for most of the 340 reported variants.

El Tor Biotype Activates the Caspase-11-Independent Canonical Nlrp3 and Pyrin Inflammasomes.

is a Gram-negative enteropathogen causing potentially life-threatening cholera disease outbreaks, for which the World Health Organization currently registers 2-4 million cases and ~100.000 cholera-associated deaths annually worldwide. Genomic research revealed that the strains causing this ongoing cholera pandemic are members of the El Tor biotype, which fully replaced the Classical biotype that caused former cholera pandemics.

Correction to: Three-dimensional reconstruction of the distribution of elemental tags in single cells using laser ablation ICP-mass spectrometry via registration approaches.

The authors would like to call the reader's attention to the fact that unfortunately the originally provided affiliation for Dr. Tomoko Asaoka was not correct.

Three-dimensional reconstruction of the distribution of elemental tags in single cells using laser ablation ICP-mass spectrometry via registration approaches.

This paper describes a workflow towards the reconstruction of the three-dimensional elemental distribution profile within human cervical carcinoma cells (HeLa), at a spatial resolution down to 1 μm, employing state-of-the-art laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) instrumentation. The suspended cells underwent a series of fixation/embedding protocols and were stained with uranyl acetate and an Ir-based DNA intercalator. A priori, laboratory-based absorption micro-computed tomography (μ-CT) was applied to acquire a reference frame of the morphology of the cells and their spatial distribution before sectioning.

Linear ubiquitination by LUBEL has a role in Drosophila heat stress response.

The HOIP ubiquitin E3 ligase generates linear ubiquitin chains by forming a complex with HOIL-1L and SHARPIN in mammals. Here, we provide the first evidence of linear ubiquitination induced by a HOIP orthologue in Drosophila We identify Drosophila CG11321, which we named Linear Ubiquitin E3 ligase (LUBEL), and find that it catalyzes linear ubiquitination in vitro We detect endogenous linear ubiquitin chain-derived peptides by mass spectrometry in Drosophila Schneider 2 cells and adult flies. Furthermore, using CRISPR/Cas9 technology, we establish linear ubiquitination-defective flies by mutating residues essential for the catalytic activity of LUBEL Linear ubiquitination signals accumulate upon heat shock in flies.

Inhibition of CBLB protects from lethal Candida albicans sepsis.

Fungal infections claim an estimated 1.5 million lives each year. Mechanisms that protect from fungal infections are still elusive.

New Insights into the Role of Ubiquitin Networks in the Regulation of Antiapoptosis Pathways.

Ubiquitin is a small modifier protein that conjugates on lysine (Lys) residues of substrates, and it can be targeted by another ubiquitin molecule to form chains through conjugation on the intrinsic Lys residues and methionine (Met) 1 residue. Ubiquitination of substrates by such chains determines the fate of substrates, thereby influencing various biological processes. In this chapter, we focus on apoptosis with an emphasis on the regulation by ubiquitination.

The c-FLIPL cleavage product p43FLIP promotes activation of extracellular signal-regulated kinase (ERK), nuclear factor κB (NF-κB), and caspase-8 and T cell survival.

Caspase-8 is now appreciated to govern both apoptosis following death receptor ligation and cell survival and growth via inhibition of the Ripoptosome. Cells must therefore carefully regulate the high level of caspase-8 activity during apoptosis versus the modest levels observed during cell growth. The caspase-8 paralogue c-FLIP is a good candidate for a molecular rheostat of caspase-8 activity.

Modeling reveals that dynamic regulation of c-FLIP levels determines cell-to-cell distribution of CD95-mediated apoptosis.

The expression levels of caspase-8 inhibitory c-FLIP proteins play an important role in regulating death receptor-mediated apoptosis, as their concentration at the moment when the death-inducing signaling complex (DISC) is formed determines the outcome of the DISC signal. Experimental studies have shown that c-FLIP proteins are subject to dynamic turnover and that their stability and expression levels can be rapidly altered. Even though the influence of c-FLIP on the apoptotic behavior of a single cell has been captured in mathematical simulation studies, the effect of c-FLIP turnover and stability has not been investigated.