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Autophagy is a lysosomal degradation pathway that degrades damaged or superfluous cell components into basic biomolecules, which are then recycled back into the cytosol. In this respect, autophagy drives a flow of biomolecules in a continuous degradation-regeneration cycle. Autophagy is generally considered a pro-survival mechanism pro- tecting cells under stress or poor nutrient conditions. Current research clearly shows that autophagy fulfills numer- ous functions in vital biological processes. It is implicated in development, differentiation, innate and adaptive immu- nity, ageing and cell death. In addition, accumulating evidence demonstrates interesting links between autophagy and several human diseases and tumor development. Therefore, autophagy seems to be an important player in the life and death of cells and organisms. Despite the mounting knowledge about autophagy, the mechanisms through which the autophagic machinery regulates these diverse processes are not entirely understood. In this review, we give a comprehensive overview of the autophagic signaling pathway, its role in general cellular processes and its connection to cell death. In addition, we present a brief overview of the possible contribution of defective autophagic signaling to disease.

Self-renewing tissue-resident macrophages are thought to be exclusively derived from embryonic progenitors. However, whether circulating monocytes can also give rise to such macrophages has not been formally investigated. Here we use a new model of diphtheria toxin-mediated depletion of liver-resident Kupffer cells to generate niche availability and show that circulating monocytes engraft in the liver, gradually adopt the transcriptional profile of their depleted counterparts and become long-lived self-renewing cells. Underlining the physiological relevance of our findings, circulating monocytes also contribute to the expanding pool of macrophages in the liver shortly after birth, when macrophage niches become available during normal organ growth. Thus, like embryonic precursors, monocytes can and do give rise to self-renewing tissue-resident macrophages if the niche is available to them. Tissue-resident macrophages are mostly derived from embryonic progenitors. Scott et al . develop a mouse model to specifically deplete Kupffer cells (KC) in vivo and show that monocyte-derived cells can repopulate KC niche and behave similar to their embryonically-derived counterparts.

The recent advent of 3D in electron microscopy (EM) has allowed for detection of nanometer resolution structures. This has caused an explosion in dataset size, necessitating the development of automated workflows. Moreover, large 3D EM datasets typically require hours to days to be acquired and accelerated imaging typically results in noisy data. Advanced denoising techniques can alleviate this, but tend to be less accessible to the community due to low-level programming environments, complex parameter tuning or a computational bottleneck. We present DenoisEM: an interactive and GPU accelerated denoising plugin for ImageJ that ensures fast parameter tuning and processing through parallel computing. Experimental results show that DenoisEM is one order of magnitude faster than related software and can accelerate data acquisition by a factor of 4 without significantly affecting data quality. Lastly, we show that image denoising benefits visualization and (semi-)automated segmentation and analysis of ultrastructure in various volume EM datasets. Large 3D electron microscopy data sets frequently contain noisy data due to accelerated imaging, and denoising techniques require specialised skill sets. Here the authors introduce DenoisEM, an ImageJ plugin that democratises denoising EM data sets, enabling fast parameter tuning and processing through parallel computing.

There is a growing appreciation that membrane-bound organelles in eukaryotic cells communicate directly with one another through direct membrane contact sites. Mitochondria-associated membranes are specialized subdomains of the endoplasmic reticulum that function as membrane contact sites between the endoplasmic reticulum and mitochondria. These sites have emerged as major players in lipid metabolism and calcium signaling. More recently also autophagy and mitochondrial dynamics have been found to be regulated at ER-mitochondria contact sites. Neurons critically depend on mitochondria-associated membranes as a means to exchange metabolites and signaling molecules between these organelles. This is underscored by the fact that genes affecting mitochondrial and endoplasmic reticulum homeostasis are clearly overrepresented in several hereditary neurodegenerative disorders. Conversely, the processes affected by the contact sites between the endoplasmic reticulum and mitochondria are widely implicated in neurodegeneration. This review will focus on the most recent data addressing the structural composition and function of the mitochondria-associated membranes. In addition, the 3D morphology of the contact sites as observed using volume electron microscopy is discussed. Finally, it will highlight the role of several key proteins associated with these contact sites that are involved not only in dementias, amyotrophic lateral sclerosis and Parkinson’s disease, but also in axonopathies such as hereditary spastic paraplegia and Charcot–Marie–Tooth disease.

Microglia, the mononuclear phagocytes of the central nervous system (CNS), are important for the maintenance of CNS homeostasis, but also critically contribute to CNS pathology. Here we demonstrate that the nuclear factor kappa B (NF-κB) regulatory protein A20 is crucial in regulating microglia activation during CNS homeostasis and pathology. In mice, deletion of A20 in microglia increases microglial cell number and affects microglial regulation of neuronal synaptic function. Administration of a sublethal dose of lipopolysaccharide induces massive microglia activation, neuroinflammation, and lethality in mice with microglia-confined A20 deficiency. Microglia A20 deficiency also exacerbates multiple sclerosis (MS)-like disease, due to hyperactivation of the Nlrp3 inflammasome leading to enhanced interleukin-1β secretion and CNS inflammation. Finally, we confirm a Nlrp3 inflammasome signature and IL-1β expression in brain and cerebrospinal fluid from MS patients. Collectively, these data reveal a critical role for A20 in the control of microglia activation and neuroinflammation. As resident macrophages of the brain, microglia are important for neuroinflammatory responses. This work shows that nuclear factor kappa B regulatory protein A20 is important for microglia activation and regulation during inflammation of the central nervous system.

Prevention of inflammatory bowel disease (IBD) relies on tight control of inflammatory, cell death and autophagic mechanisms, but how these pathways are integrated at the molecular level is still unclear. Here we show that the anti-inflammatory protein A20 and the critical autophagic mediator Atg16l1 physically interact and synergize to regulate the stability of the intestinal epithelial barrier. A proteomic screen using the WD40 domain of ATG16L1 (WDD) identified A20 as a WDD-interacting protein. Loss of A20 and Atg16l1 in mouse intestinal epithelium induces spontaneous IBD-like pathology, as characterized by severe inflammation and increased intestinal epithelial cell death in both small and large intestine. Mechanistically, absence of A20 promotes Atg16l1 accumulation, while elimination of Atg16l1 or expression of WDD-deficient Atg16l1 stabilizes A20. Collectively our data show that A20 and Atg16l1 cooperatively control intestinal homeostasis by acting at the intersection of inflammatory, autophagy and cell death pathways. Maintaining the intestinal barrier function requires a balance of multiple signalling pathways. Here the authors show that A20, an anti-inflammatory and anti-apoptotic protein, and Atg1611, an autophagy regulator, cross-regulate their respective protein levels and function to serve compensatory and redundant roles in fine-tuning gut barrier homeostasis.

Alzheimer's disease (AD) is the most common form of dementia, and neuroinflammation is an important hallmark of the pathogenesis. Tumor necrosis factor (TNF) might be detrimental in AD, though the results coming from clinical trials on anti‐TNF inhibitors are inconclusive. TNFR1, one of the TNF signaling receptors, contributes to the pathogenesis of AD by mediating neuronal cell death. The blood–cerebrospinal fluid (CSF) barrier consists of a monolayer of choroid plexus epithelial (CPE) cells, and AD is associated with changes in CPE cell morphology. Here, we report that TNF is the main inflammatory upstream mediator in choroid plexus tissue in AD patients. This was confirmed in two murine AD models: transgenic APP/PS1 mice and intracerebroventricular (icv) AβO injection. TNFR1 contributes to the morphological damage of CPE cells in AD, and TNFR1 abrogation reduces brain inflammation and prevents blood–CSF barrier impairment. In APP/PS1 transgenic mice, TNFR1 deficiency ameliorated amyloidosis. Ultimately, genetic and pharmacological blockage of TNFR1 rescued from the induced cognitive impairments. Our data indicate that TNFR1 is a promising therapeutic target for AD treatment. Synopsis Increased TNF/TNFR1 signaling plays a detrimental role in Alzheimer's disease pathology and is associated with morphological alterations at the choroid plexus in patients and mice, and neuroinflammation. Blocking TNFR1 signaling prevents cognitive decline in Alzheimer's disease mouse models. TNF/TNFR1 signaling is activated in the choroid plexus of late‐stage Alzheimer's disease patients. Increased TNFR1 signaling contributes to morphological alterations in choroid plexus epithelial cells. TNFR1 deficiency prevents neuroinflammation and amyloidogenesis, and reduces microgliosis in Alzheimer's disease mouse models. Genetic and pharmacological blockage of TNFR1 signaling prevents cognitive decline in Alzheimer's disease mouse models. Graphical Abstract Increased TNF/TNFR1 signaling plays a detrimental role in Alzheimer's disease pathology and is associated with morphological alterations at the choroid plexus in patients and mice, and neuroinflammation. Blocking TNFR1 signaling prevents cognitive decline in Alzheimer's disease mouse models.

Caspase-14 is a protease that is mainly expressed in suprabasal epidermal layers and activated during keratinocyte cornification. Caspase-14-deficient mice display reduced epidermal barrier function and increased sensitivity to UVB radiation. In these mice, profilaggrin, a protein with a pivotal role in skin barrier function, is processed correctly to its functional filaggrin (FLG) repeat unit, but proteolytic FLG fragments accumulate in the epidermis. In wild-type stratum corneum, FLG is degraded into free amino acids, some of which contribute to generation of the natural moisturizing factors (NMFs) that maintain epidermal hydration. We found that caspase-14 cleaves the FLG repeat unit and identified two caspase-14 cleavage sites. These results indicate that accumulation of FLG fragments in caspase-14-/- mice is due to a defect in the terminal FLG degradation pathway. Consequently, we show that the defective FLG degradation in caspase-14-deficient skin results in substantial reduction in the amount of NMFs, such as urocanic acid and pyrrolidone carboxylic acid. Taken together, we identified caspase-14 as a crucial protease in FLG catabolism.

Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting memory and cognition. The disease is accompanied by an abnormal deposition of ß-amyloid plaques in the brain that contributes to neurodegeneration and is known to induce glial inflammation. Studies in the mouse model of ß-amyloid-induced neuropathology have suggested a role for inflammasome activation in ß-amyloid-induced neuroinflammation and neuropathology. Here, we evaluated the role of microglia-selective and full body inflammasome signalling in several mouse models of ß-amyloid-induced AD neuropathology. Microglia-specific deletion of the inflammasome regulator A20 and inflammasome effector protease caspase-1 in the and models failed to identify a prominent role for microglial inflammasome signalling in ß-amyloid-induced neuropathology. Moreover, global inflammasome inactivation through respectively full body deletion of caspases 1 and 11 in mice and Nlrp3 deletion in mice also failed to modulate amyloid pathology and disease progression. In agreement, single-cell RNA sequencing did not reveal an important role for Nlrp3 signalling in driving microglial activation and the transition into disease-associated states, both during homeostasis and upon amyloid pathology. Collectively, these results question a generalizable role for inflammasome activation in preclinical amyloid-only models of neuroinflammation.

The RIP kinases have emerged as essential mediators of cellular stress that integrate both extracellular stimuli emanating from various cell-surface receptors and signals coming from intracellular pattern recognition receptors. The molecular mechanisms regulating the ability of the RIP proteins to transduce the stress signals remain poorly understood, but seem to rely only partially on their kinase activities. Recent studies on RIP1 and RIP2 have highlighted the importance of ubiquitination as a key process regulating their capacity to activate downstream signaling pathways. In this study, we found that XIAP, cIAP1 and cIAP2 not only directly bind to RIP1 and RIP2 but also to RIP3 and RIP4. We show that cIAP1 and cIAP2 are direct E3 ubiquitin ligases for all four RIP proteins and that cIAP1 is capable of conjugating the RIPs with diverse types of ubiquitin chains, including linear chains. Consistently, we show that repressing cIAP1/2 levels affects the activation of NF-κB that is dependent on RIP1, -2, -3 and -4. Finally, we identified Lys51 and Lys145 of RIP4 as two critical residues for cIAP1-mediated ubiquitination and NF-κB activation.