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