TspanC8 tetraspanins have a conserved function in the regulation of ADAM10 trafficking and activity, thereby positively regulating Notch activation.

SUMMARY Constitutive cell-autonomous immunity in metazoans predates interferon-inducible immunity and comprises primordial innate defense. Phagocytes mobilize interferon-inducible responses upon engagement of well-characterized signaling pathways by pathogen-associated molecular patterns (PAMPs). The signals controlling deployment of constitutive cell-autonomous responses during infection have remained elusive. Vita-PAMPs denote microbial viability, signaling the danger of cellular exploitation by intracellular pathogens. We show that cyclic-di-adenosine monophosphate in live Gram-positive bacteria is a vita-PAMP engaging the innate sensor Stimulator of Interferon Genes (STING) to mediate endoplasmic reticulum (ER) stress. Subsequent inactivation of the mechanistic Target of Rapamycin mobilizes autophagy, which sequesters stressed ER membranes, resolves ER stress, and curtails phagocyte death. This vita-PAMP-induced ER-phagy additionally orchestrates an interferon response by localizing ER-resident STING to autophagosomes. Our findings identify stress-mediated ER-phagy as a cell-autonomous response mobilized by STING-dependent sensing of a specific vita-PAMP, and elucidate how innate receptors engage multilayered homeostatic mechanisms to promote immunity and survival after infection.

The translation initiation factor complex eIF3f has an intrinsic deubiquitinase activity and regulates the Notch signaling pathway.

Highlights d Non-cleavable caspase-8 (caspase-8 DA) causes inflammation, blocked by necroptosis d Inflammation in Casp8 DA/DA Mlkl À/À mice is prevented by ablation of one allele of Fadd d Full deletion of Fadd in Casp8 DA/DA Mlkl À/À mice causes Casp1-dependent lethality d Non-cleavable caspase-8 induces ASC oligomerization in absence of FADD

A decade of work shows that the core function of phagocytosis in engulfment and destruction of microorganisms is only a small facet of the full spectrum of roles for phagocytosis in the immune system. The regulation of phagocytosis and its outcomes by inflammatory pattern recognition receptors (PRRs) is now followed by new studies strengthening this concept and adding further complexity to the relationship between phagocytosis and innate immune signaling. Phagocytosis forms the platform for activation of distinct members of the Toll-like receptor family, and even dictates their signaling outcomes. In many cases, phagocytosis is a necessary precedent to the activation of cytosolic PRRs and assembly of canonical and non-canonical inflammasomes, leading to strong pro-inflammatory responses and inflammatory cell death.

Inflammasomes are multiprotein complexes that assemble upon detection of danger signals to activate the inflammatory enzyme caspase‐1, trigger secretion of the highly proinflammatory cytokine IL‐1β, and induce an inflammatory cell death called pyroptosis. Distinctiveness of the nucleotide‐binding oligomerization (NOD), Leucine‐rich repeat (LRR)‐containing protein (NLRP3) inflammasome resides in the diversity of molecules that induce its activation, indicating a certain intricacy. Furthermore, besides the canonical activation of NLRP3 in response to various stimuli, caspase‐11‐dependent detection of intracellular LPS activates NLRP3 through a noncanonical pathway. Several aspects of the NLRP3 inflammasome are not characterized or remain unclear. In this review, we summarize the different modes of NLRP3 activation. We describe recent insights into post‐translational and cellular regulation that confer further complexity to NLRP3 inflammasomes.

The very conserved Notch pathway is used iteratively during development and adulthood to regulate cell fates. Notch activation relies on interactions between neighboring cells, through the binding of Notch receptors to their ligands, both transmembrane molecules. This inter-cellular contact initiates a cascade of events eventually transforming the cell surface receptor into a nuclear factor acting on the transcription of specific target genes. This review highlights how the various processes undergone by Notch receptors and ligands that regulate the pathway are linked to ubiquitination events.

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