Mitochondrial chaperone <scp>HSP</scp>‐60 regulates anti‐bacterial immunity via p38 <scp>MAP</scp> kinase signaling

Jeong, Dae‐Eun; Lee, Dong-Yeop; Hwang, Sunyoung; Lee, Yujin; Lee, Jee Eun; Seo, Mihwa; Hwang, Wooseon; Seo, Keunhee; Hwang, Ara B.; Artan, Murat; Son, Heehwa G.; Jo, Jay‐Hyun; Baek, Haeshim; Oh, Yonghwan; Ryu, Youngjae; Kim, Hyung‐Jun; Ha, Chang Man; Yoo, Joo‐Yeon; Lee, Seung‐Jae V

doi:10.15252/embj.201694781

Cited by 74 publications

(74 citation statements)

References 88 publications

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“…In this study, we found that C. elegans starts to avoid the pathogenic bacterium P. aeruginosa within 30 min of exposure. This avoidance seems to be a very quick response compared to previous reports concerning avoidance of PA14, which is clearly observed from 8 to 16 hr after exposure (Hao et al, 2018;Jeong et al, 2017). Furthermore, we isolated a mutant defective in this quick avoidance behavior to PA14.…”

Section: Discussionsupporting

confidence: 45%

Intestinal F‐box protein regulates quick avoidance behavior of Caenorhabditis elegans to the pathogenic bacterium Pseudomonas aeruginosa

2019

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In most animals, avoiding pathogenic bacteria is crucial for better health and a long life span. For this purpose, animals should be able to quickly sense the presence or uptake of pathogens. The intestine could be a candidate organ to induce escape behaviors; however, the intestinal signaling mechanism for acute regulation of neuronal activity is not well understood. Here, we show that adult Caenorhabditis elegans can respond to the pathogenic bacterium Pseudomonas aeruginosa within 30 min of exposure. This behavior was much faster than previously observed avoidance behaviors in response to P. aeruginosa. By genetic screening, we isolated a mutant defective in this quick avoidance behavior and found that the novel F‐box protein FBXC‐58 is involved. FBXC‐58 is expressed in several tissues, but defective avoidance was rescued by expression of the protein in the intestine. Interestingly, we also found that some but not all mutants in the p38‐MAPK and insulin‐like signaling pathways, which function in the immune response to pathogens in the intestine, were defective in the quick avoidance behavior to P. aeruginosa. These results suggest that a novel signaling pathway in the intestine exists to regulate neuronal activity for a quick behavioral response.

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Section: Discussionsupporting

confidence: 45%

Intestinal F‐box protein regulates quick avoidance behavior of Caenorhabditis elegans to the pathogenic bacterium Pseudomonas aeruginosa

2019

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“…Various microbes such as the opportunistic pathogen Pseudomonas aeruginosa can activate the UPR mt through the production of mitochondrial toxins (18,45). Consistent with a role in protecting the host from infection, ATFS-1 is required and sufficient for survival during P. aeruginosa infection (45,46). Interestingly, the mitochondrial chaperone HSP-60 that is transcriptionally up-regulated during the UPR mt by ATFS-1 (7, 10, 11) promotes host resistance during infection by enhancing the PMK-1/p38 MAPK innate immunity pathway through direct binding and stabilization of SEK-1/MAPK kinase 3 (46).…”

Section: Protection Against Pathogen Infectionmentioning

confidence: 97%

The mitochondrial unfolded protein response: Signaling from the powerhouse

Qureshi

Haynes

Pellegrino

2017

Journal of Biological Chemistry

125

118

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Edited by Ruma BanerjeeMitochondria are multifaceted and indispensable organelles required for cell performance. Accordingly, dysfunction to mitochondria can result in cellular decline and possibly the onset of disease. Cells use a variety of means to recover mitochondria and restore homeostasis, including the activation of retrograde pathways such as the mitochondrial unfolded protein response (UPR mt ). In this Minireview, we will discuss how cells adapt to mitochondrial stress through UPR mt regulation. Furthermore, we will explore the current repertoire of biological functions that are associated with this essential stress-response pathway.Mitochondria are double membrane organelles commonly associated with the production of cellular energy via oxidative phosphorylation (OXPHOS).2 Mitochondria are also required for the metabolism of nucleotides, amino acids, and lipids and have an essential function in regulating apoptosis. Maintaining mitochondrial integrity is therefore a key aspect in ensuring cellular and organismal viability. Consequently, a decline in mitochondrial function is frequently associated with the development of numerous diseases (1).Mitochondria are dependent on a diverse compilation of proteins to carry out their vital functions. However, the mitochondrial proteome is faced with various challenges, most notably the partitioning of protein encoding genes between the mitochondrial and nuclear genomes. Remarkably, the human mitochondrial genome only encodes ϳ1% of the total mitochondrial proteome with the remaining proteins being encoded by nuclear genes (2). Sophisticated mechanisms have evolved to efficiently transfer nuclear-encoded mitochondrial proteins to their proper organelle destination following translation on cytosolic ribosomes. To accomplish this complex task, proteins are sorted to mitochondria via targeting sequences that form characteristic amphipathic helices composed of positively charged residues. Such mitochondrial targeting sequences (MTS) are recognized and translocated via the mitochondrial Tom-Tim complex to their respective sub-organelle compartment (3). Exquisite coordination of expression between the mitochondrial and nuclear genomes exists during mitochondrial biogenesis, as failure in genome coordination can disrupt the precise stoichiometry of these OXPHOS complexes resulting in orphan subunit accumulation and proteotoxicity (4). Further contributing to mitochondrial proteotoxicity is the possible damage to the mitochondrial genome from reactive oxygen species (ROS) produced by OXPHOS machinery as well as the ill effects of various environmental toxins. Mechanisms must therefore exist to ensure the protection of the mitochondrial proteome.Quality control of the mitochondrial proteome includes the functions of mitochondrial chaperones that assist in proper protein folding and proteases that promote clearance of misfolded proteins (5). Each sub-compartment of mitochondria houses its own quality control machinery to ensure protein homeostasis and organelle function. ...

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“…MAPK (Cell Signaling #4511), anti-Histone H3 (Cell Signaling #9715), anti-alpha tubulin (abcam ab40742). phospho-PMK-1 western blot assays were performed as described in 71 .…”

Section: Immunoblottingmentioning

confidence: 99%

MALT1 mediates IL-17 Neural Signaling to regulate C. elegansbehavior, immunity and longevity

Flynn

Chen

Artan

et al. 2019

Preprint

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Besides well-known immune roles, the evolutionarily ancient cytokine interleukin-17 (IL-17) modulates neural circuit function. We investigate how IL-17 signals in neurons, and the extent to which this signaling can alter organismal phenotypes.We combine immunoprecipitation and mass spectrometry to biochemically characterize endogenous signaling complexes that function downstream of IL-17 receptors in C. elegans (Ce) neurons. We identify the Ce ortholog of MALT1 as a critical output of the pathway. MALT1 was not previously implicated in IL-17 signaling or in nervous system function. MALT1 forms a complex with homologs of Act1 and IRAK and functions both as a scaffold for IκB recruitment, and as a protease. MALT1 is expressed broadly in the Ce nervous system, and neuronal IL-17-MALT1 signaling regulates many phenotypes, including escape behavior, associative learning, immunity and longevity. Our data suggest MALT1 has an ancient role modulating neural function downstream of IL-17 to remodel physiological and behavioral state.To confirm these biochemical interactions we expressed functional, GFP-tagged MALT1 pan-neuronally, and identified interacting partners using IP/MS of extracts from the transgenic Ce strain. As a control, we performed IP/MS on extracts from strains expressing GFP-tagged neuronal proteins unrelated to IL-17 signaling. ACTL-1, PIK-1 and NFKI-1 each interacted specifically with MALT-1-GFP ( Fig. 1e). We also identified other specific interactors ( Supplementary Table 1d) including the Ce ortholog of mammalian SARM1, called TIR-1, which is implicated in the immune response 24,25 , left/right asymmetry of an olfactory neuron 26 , and experience-dependent plasticity 27 . MALT-1 also interacted specifically with a large group of proteins implicated in RNA metabolism, including splicing factors and polyA binding proteins, suggesting it may localize to the nucleus or ribonucleoprotein particles (RNPs) ( Supplementary Fig. 3). MALT-1 promotes C. elegans aggregation and escape from 21% O 2Previous work has not implicated MALT1 in IL-17 signaling or neural function. In Ce, the IL-17 ILC-17.1 signals through the ILCR-1/ILCR-2 receptors on the RMG interneurons to increase RMG responsiveness to input from their pre-synaptic partner, the URX O 2 -sensing neurons (Fig. 1f). Increased RMG signaling enables Ce to strongly and persistently escape 21% O 2 and to aggregate 17,28,29 . To probe the functional relevance of our proteomics data we asked if the large collection of mutants that yielded IL-17 pathway mutants 17 included malt-1 loss-of-function alleles. This collection was isolated in a forward genetic screen for mutants

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Mitochondrial chaperone HSP‐60 regulates anti‐bacterial immunity via p38 MAP kinase signaling

Cited by 74 publications

References 88 publications

Intestinal F‐box protein regulates quick avoidance behavior of Caenorhabditis elegans to the pathogenic bacterium Pseudomonas aeruginosa

Intestinal F‐box protein regulates quick avoidance behavior of Caenorhabditis elegans to the pathogenic bacterium Pseudomonas aeruginosa

The mitochondrial unfolded protein response: Signaling from the powerhouse

MALT1 mediates IL-17 Neural Signaling to regulate C. elegansbehavior, immunity and longevity

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