scholarly journals Mild impairment of mitochondrial function increases longevity and pathogen resistance through ATFS-1-driven activation of p38-regulated innate immunity

2021 ◽  
Author(s):  
Juliane Campos ◽  
Ziyun Wu ◽  
Paige D Rudich ◽  
Sonja Soo ◽  
Meeta Mistry ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Mitochondrial Function ◽  
Innate Immune ◽  
Unfolded Protein ◽  
Innate Immune Signaling ◽  
Immune Signaling Pathway ◽  
Mild Impairment ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response ◽  
Innate Immune Signaling Pathway

While mitochondrial function is essential for life in all multicellular organisms, a mild impairment of mitochondrial function can extend longevity. By understanding the molecular mechanisms involved, these pathways might be targeted to promote healthy aging. In studying two long-lived mitochondrial mutants in C. elegans, we found that disrupting subunits of the mitochondrial electron transport chain resulted in upregulation of genes involved in innate immunity, which we found to be dependent on not only the canonical p38-mediated innate immune signaling pathway but also on the mitochondrial unfolded protein response. Both of these pathways are absolutely required for the increased resistance to bacterial pathogens and extended longevity of the long-lived mitochondrial mutants, as is the FOXO transcription factor DAF-16. This work demonstrates that both the p38-mediated innate immune signaling pathway and the mitochondrial unfolded protein response can act on the same innate immunity genes to promote resistance to bacterial pathogens, and that input from the mitochondria can extend longevity by signaling through these two pathways. Combined, this indicates that multiple evolutionarily conserved genetic pathways controlling innate immunity also function to modulate lifespan.

The heme-regulated inhibitor is a cytosolic sensor of protein misfolding that controls innate immune signaling

Science ◽  
2019 ◽  
Vol 365 (6448) ◽  
pp. eaaw4144 ◽  
Author(s):  
Mena Abdel-Nour ◽  
Leticia A. M. Carneiro ◽  
Jeffrey Downey ◽  
Jessica Tsalikis ◽  
Ahmed Outlioua ◽  
...  
Keyword(s):  
Protein Misfolding ◽  
Innate Immune ◽  
Initiation Factor ◽  
Immune Signaling ◽  
Unfolded Protein ◽  
Immune Mediators ◽  
Innate Immune Signaling ◽  
Signaling Axis ◽  
Eif2α Kinase ◽  
Protein Response

Multiple cytosolic innate sensors form large signalosomes after activation, but this assembly needs to be tightly regulated to avoid accumulation of misfolded aggregates. We found that the eIF2α kinase heme-regulated inhibitor (HRI) controls NOD1 signalosome folding and activation through a process requiring eukaryotic initiation factor 2α (eIF2α), the transcription factor ATF4, and the heat shock protein HSPB8. The HRI/eIF2α signaling axis was also essential for signaling downstream of the innate immune mediators NOD2, MAVS, and TRIF but dispensable for pathways dependent on MyD88 or STING. Moreover, filament-forming α-synuclein activated HRI-dependent responses, which suggests that the HRI pathway may restrict toxic oligomer formation. We propose that HRI, eIF2α, and HSPB8 define a novel cytosolic unfolded protein response (cUPR) essential for optimal innate immune signaling by large molecular platforms, functionally homologous to the PERK/eIF2α/HSPA5 axis of the endoplasmic reticulum UPR.

CS17-5. Arteri- and nairovirus OTU domain-containing proteases target ubiquitin-regulated factors in the RLR-mediated innate immune signaling pathway

Cytokine ◽  
2011 ◽  
Vol 56 (1) ◽  
pp. 108
Author(s):  
Marjolein Kikkert ◽  
Puck B. van Kasteren ◽  
Corrine Beugeling ◽  
Dennis Ninaber ◽  
Sander van Boheemen ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Innate Immune ◽  
Immune Signaling ◽  
Innate Immune Signaling ◽  
Immune Signaling Pathway ◽  
Innate Immune Signaling Pathway

scholarly journals Thein VitroEffects of Resistin on the Innate Immune Signaling Pathway in Isolated Human Subcutaneous Adipocytes

2007 ◽  
Vol 92 (1) ◽  
pp. 270-276 ◽  
Author(s):  
Christine M. Kusminski ◽  
Nancy F. da Silva ◽  
Steven J. Creely ◽  
Ffolliott M. Fisher ◽  
Alison L. Harte ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Innate Immune ◽  
Immune Signaling ◽  
Innate Immune Signaling ◽  
Immune Signaling Pathway ◽  
Innate Immune Signaling Pathway

scholarly journals Sensing, signaling and surviving mitochondrial stress

2021 ◽  
Author(s):  
Eva-Maria Eckl ◽  
Olga Ziegemann ◽  
Luisa Krumwiede ◽  
Evelyn Fessler ◽  
Lucas T. Jae
Keyword(s):  
Mitochondrial Function ◽  
Building Blocks ◽  
Mitochondrial Network ◽  
Mitochondrial Proteome ◽  
Unfolded Protein ◽  
Proteotoxic Stress ◽  
Control Factors ◽  
Different Types ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

AbstractMitochondrial fidelity is a key determinant of longevity and was found to be perturbed in a multitude of disease contexts ranging from neurodegeneration to heart failure. Tight homeostatic control of the mitochondrial proteome is a crucial aspect of mitochondrial function, which is severely complicated by the evolutionary origin and resulting peculiarities of the organelle. This is, on one hand, reflected by a range of basal quality control factors such as mitochondria-resident chaperones and proteases, that assist in import and folding of precursors as well as removal of aggregated proteins. On the other hand, stress causes the activation of several additional mechanisms that counteract any damage that may threaten mitochondrial function. Countermeasures depend on the location and intensity of the stress and on a range of factors that are equipped to sense and signal the nature of the encountered perturbation. Defective mitochondrial import activates mechanisms that combat the accumulation of precursors in the cytosol and the import pore. To resolve proteotoxic stress in the organelle interior, mitochondria depend on nuclear transcriptional programs, such as the mitochondrial unfolded protein response and the integrated stress response. If organelle damage is too severe, mitochondria signal for their own destruction in a process termed mitophagy, thereby preventing further harm to the mitochondrial network and allowing the cell to salvage their biological building blocks. Here, we provide an overview of how different types and intensities of stress activate distinct pathways aimed at preserving mitochondrial fidelity.

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