Intracellular double-stranded RNA (dsRNA) is a chief sign of replication for many viruses. Host mechanisms detect the dsRNA and initiate antiviral responses. In this report, we identify retinoic acid inducible gene I (RIG-I), which encodes a DExD/H box RNA helicase that contains a caspase recruitment domain, as an essential regulator for dsRNA-induced signaling, as assessed by functional screening and assays. A helicase domain with intact ATPase activity was responsible for the dsRNA-mediated signaling. The caspase recruitment domain transmitted 'downstream' signals, resulting in the activation of transcription factors NF-kappaB and IRF-3. Subsequent gene activation by these factors induced antiviral functions, including type I interferon production. Thus, RIG-I is key in the detection and subsequent eradication of the replicating viral genomes.

The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

https://biblio.ugent.be/publication/8555786/file/8555788.pdf

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

■ Abstract Apoptosis is a genetically programmed, morphologically distinct form of cell death that can be triggered by a variety of physiological and pathological stimuli. Studies performed over the past 10 years have demonstrated that proteases play critical roles in initiation and execution of this process. The caspases, a family of cysteine-dependent aspartate-directed proteases, are prominent among the death proteases. Caspases are synthesized as relatively inactive zymogens that become activated by scaffold-mediated transactivation or by cleavage via upstream proteases in an intracellular cascade. Regulation of caspase activation and activity occurs at several different levels: ( a) Zymogen gene transcription is regulated; ( b) antiapoptotic members of the Bcl-2 family and other cellular polypeptides block proximity-induced activation of certain procaspases; and ( c) certain cellular inhibitor of apoptosis proteins (cIAPs) can bind to and inhibit active caspases. Once activated, caspases cleave a variety of intracellular polypeptides, including major structural elements of the cytoplasm and nucleus, components of the DNA repair machinery, and a number of protein kinases. Collectively, these scissions disrupt survival pathways and disassemble important architectural components of the cell, contributing to the stereotypic morphological and biochemical changes that characterize apoptotic cell death.

Mammalian caspases: structure ,a ctivation ,s ubstrates, and functions during apoptosis

In 2009, the Nomenclature Committee on Cell Death (NCCD) proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related terminology, including 'apoptosis', 'necrosis' and 'mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.

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Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012

Interleukin 6 (IL-6) has a broad effect on cells of the immune system and those not of the immune system and often displays hormone-like characteristics that affect homeostatic processes. IL-6 has context-dependent pro- and anti-inflammatory properties and is now regarded as a prominent target for clinical intervention. However, the signaling cassette that controls the activity of IL-6 is complicated, and distinct intervention strategies can inhibit this pathway. Clinical experience with antagonists of IL-6 has raised new questions about how and when to block this cytokine to improve disease outcome and patient wellbeing. Here we discuss the effect of IL-6 on innate and adaptive immunity and the possible advantages of various antagonists of IL-6 and consider how the immunobiology of IL-6 may inform clinical decisions.

/pdf/il-6-as-a-keystone-cytokine-in-health-and-disease-c7lxehv1qz.pdf

IL-6 as a keystone cytokine in health and disease

Identification of the proteinaceous components of the pathological inclusions is an important step in understanding the associated disease mechanisms. We immunohistochemically examined two previously reported cases with eosinophilic neuronal cytoplasmic inclusions (NCIs)(case 1, Mori et al. Neuropathology 2010; 30: 648–53; case 2, Kojima et al. Acta Pathol Jpn 1990; 40: 785–91) using 67 antibodies against proteins related to cytoskeletal constituents, ubiquitin-proteasome system, autophagy-lysosome pathway and stress granule formation. Regional distribution pattern of eosinophilic NCIs in case 1 was substantially different from that in case 2. However, NCIs in both cases were immunonegative for ubiquitin and p62 and were immunopositive for stress granule markers as well as autophagy-related proteins, including valosin-containing protein. Considering that eukaryotic stress granules are cleared by autophagy and valosin-containing protein function, our findings suggest that eosinophilic NCIs in the present two cases may represent the process of autophagic clearance of stress granules.

Ubiquitin-negative, eosinophilic neuronal cytoplasmic inclusions associated with stress granules and autophagy: an immunohistochemical investigation of two cases.

Globular glial tauopathy (GGT) is a group of 4-repeat tauopathies characterized by widespread globular glial inclusions (GGIs). GGT is now classified into three subtypes based on the distribution and morphology of the GGIs. We report an autopsy case of GGT in an 85-year-old woman who presented with semantic dementia, a rare phenotype in GGT. Postmortem examination revealed marked atrophy of the frontotemporal and motor cortices and corticospinal tract degeneration with widespread occurrence of globular neurofibrillary tangles and GGIs. The distribution of the pathology was similar to that seen in GGT type III. However, the morphology of astrocytic inclusions in the present case differed from that in type III. Moreover, the tau burden in the primary motor area was more severe in the gray than in the white matter, and globular oligodendroglial inclusions were more numerous than astrocytic inclusions, corresponding to GGT type II. By contrast, the tau pathology in the temporal lobe was chiefly globular oligodendroglial inclusions in the white matter, corresponding to GGT type I. Thus, the present case exhibited a combination of GGT types I and II pathology. Our findings appear to extend the pathological heterogeneity of GGT.

Atypical globular glial tauopathy with a combination of types I and II pathology.

Polymicrogyria (PMG) is a complex malformation accompanied with abnormal cortical laminations (two-, four- or six-layered cortex), and horizontally oriented myelinated fiber layer is evident in four-layered PMG in older individuals. Here we report a 65-year-old man with refractory epilepsy, in whom postmortem examination revealed four-layered PMG in the left hemisphere. We carried out a histological and immunohistochemical study to clarify the nature of the myelinated band in four-layered PMG cortex. The myelinated band contained no or only few neurons. GFAP- and aquaporin-1-immunoreactive astrocytes were found in the subcortical white matter as well as in the myelinated band. By contrast, GFAP- and aquaporin-1-immunoreactive astrocytes were not found in the band of Baillarger. These findings suggest that the myelinated band in PMG cortex is not the band of Baillarger and that the immunohistochemical characteristics of astrocytes in the myelinated band in PMG cortex are similar to those of the subcortical white matter. Previous studies suggest that PMG is not a cell migration disorder but a post-migration malformation. Taken together, it is likely that the myelinated band in PMG cortex represents abnormality of axonal growth or myelination after migration has terminated.

Kunikazu Tanji

Papers

Ubiquitin-negative, eosinophilic neuronal cytoplasmic inclusions associated with stress granules and autophagy: an immunohistochemical investigation of two cases.

Atypical globular glial tauopathy with a combination of types I and II pathology.

An autopsy case of refractory epilepsy due to unilateral polymicrogyria in a 65-year-old man: Histogenesis of four-layered polymicrogyric cortex.

Novel tankyrase inhibitors suppress TDP-43 aggregate formation.

Status epilepticus causing extensive microvacuolar change with astrocytosis and diffusion MRI abnormalities in the subcortical white matter.