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.
Can the innate immune system detect and respond to microbial viability? Using bacteria as a model, we found that indeed the very essence of microbial infectivity, viability itself, can be detected, and notably, in the absence of the activity of virulence factors. The microbial molecule that serves as the signature of viability is bacterial messenger RNA (mRNA), common to all bacteria, and without which bacteria cannot survive. Prokaryotic mRNAs also differ from eukaryotic mRNAs in several ways, and as such, these features all fulfill the criteria, and more, for a pathogen-associated molecular pattern (PAMP) as originally proposed by Charles Janeway. Because these mRNAs are lost from dead bacteria, they belong to a special class of PAMPs, which we call vita-PAMPs. Here we discuss the possible receptors and pathways involved in the detection of bacterial mRNAs, and thus microbial viability. We also consider examples of vita-PAMPs other than bacterial mRNA.
Black-pearl (Blp) is a highly conserved, essential inner-mitochondrial membrane protein. The yeast Blp homologue, Magmas/Pam16, is required for mitochondrial protein transport, growth, and survival. Our purpose was to determine the role of Drosophila Blp in mitochondrial function, cell survival, and proliferation. To this end, we performed mitotic recombination in Drosophila melanogaster, RNAi-mediated knockdown, MitoTracker staining, measurement of reactive oxygen species (ROS), flow cytometry, electron transport chain complex assays, and hemocyte isolation from Drosophila larvae. Proliferation-defective, Blp-deficient Drosophila Schneider cells exhibited mitochondrial membrane depolarization, a 60% decrease in ATP levels, increased amounts of ROS (3.5-fold), cell cycle arrest, and activation of autophagy that were associated with a selective 65% reduction of cytochrome c oxidase activity. N-acetyl cysteine (NAC) rescued Blp-RNAi-treated cells from cell cycle arrest, indicating that increased production of ROS is the primary cause of the proliferation and survival defects in Blp-depleted cells. blp hypomorph larvae had a 35% decreased number of plasmatocytes with a 45% reduced active mitochondrial staining and their viability was increased 2-fold by administration of NAC, which blocked melanotic lesions. Loss of Blp decreases cytochrome c oxidase activity and uncouples oxidative phosphorylation, causing ROS production, which selectively affects mitochondria-rich plasmatocyte survival and function, leading to melanotic lesions in Blp-deficient flies.
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