scholarly journals The PMK-3 (p38) Mitochondrial Retrograde Response Functions in Intestinal Cells to Extend Life via the ESCRT Machinery

2019 ◽  
Author(s):  
Oxana Radetskaya ◽  
Rebecca K. Lane ◽  
Troy Friedman ◽  
Aria Garrett ◽  
Michael Nguyen ◽  
...  
Keyword(s):  
Extracellular Vesicle ◽  
Mitogen Activated Protein Kinase ◽  
Life Extension ◽  
Endomembrane System ◽  
Escrt Machinery ◽  
Transport Chain ◽  
Mitogen Activated Protein ◽  
Signaling Axis ◽  
Core Components ◽  
Retrograde Response

ABSTRACTThe p38 mitogen-activated protein kinase (MAPK) PMK-3 controls a life-extending retrograde response in the nematode Caenorhabditis elegans that is activated following mitochondrial electron transport chain (ETC) disruption and is distinct from known longevity-promoting pathways. Here we show that the long isoform of PMK-3 expressed exclusively in the gut, rather than neurons, is sufficient to fully extend the life of animals exposed to mild ETC dysfunction. Surprisingly, constitutive activation of PMK-3 using a gain-of-function MAP3K/DLK-1 mutant does not extend the life of wild-type worms due to dampening of the DLK-1/PMK-3 signaling axis with age. We further show that core components of the ESCRT-III machinery, including ISTR-1, CHMP2B (CC01A4.2) and RAB-11.1, are required for life extension following ETC disruption. ESCRT proteins are needed for extracellular vesicle (EV) formation, lysosomal traffic and other functions requiring membrane encapsulation away from the cytoplasm. Together, our findings underscore PMK-3 as a pivotal factor controlling life extension in worms following mitochondrial ETC disruption and illustrate the importance of the endomembrane system to this process. Our findings raise the possibility that EVs may act as intra-organismal signaling vehicles to control aging.

scholarly journals Chrysin Inhibits TNFα-Induced TSLP Expression through Downregulation of EGR1 Expression in Keratinocytes

2021 ◽  
Vol 22 (9) ◽  
pp. 4350
Author(s):  
Hyunjin Yeo ◽  
Younghan Lee ◽  
Sungshin Ahn ◽  
Euitaek Jung ◽  
Yoongho Lim ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Skin Lesions ◽  
Therapeutic Agents ◽  
Mitogen Activated Protein Kinase ◽  
Necrosis Factor Alpha ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Signaling Axis ◽  
Factor Alpha ◽  
Necrosis Factor

Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that acts as a critical mediator in the pathogenesis of atopic dermatitis (AD). Various therapeutic agents that prevent TSLP function can efficiently relieve the clinical symptoms of AD. However, the downregulation of TSLP expression by therapeutic agents remains poorly understood. In this study, we investigated the mode of action of chrysin in TSLP suppression in an AD-like inflammatory environment. We observed that the transcription factor early growth response (EGR1) contributed to the tumor necrosis factor alpha (TNFα)-induced transcription of TSLP. Chrysin attenuated TNFα-induced TSLP expression by downregulating EGR1 expression in HaCaT keratinocytes. We also showed that the oral administration of chrysin improved AD-like skin lesions in the ear and neck of BALB/c mice challenged with 2,4-dinitrochlorobenzene. We also showed that chrysin suppressed the expression of EGR1 and TSLP by inhibiting the extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) 1/2 mitogen-activated protein kinase pathways. Collectively, the findings of this study suggest that chrysin improves AD-like skin lesions, at least in part, through the downregulation of the ERK1/2 or JNK1/2-EGR1-TSLP signaling axis in keratinocytes.

scholarly journals Picomolar zinc binding modulates formation of Bcl10-nucleating assemblies of the caspase recruitment domain (CARD) of CARD9

2018 ◽  
Vol 293 (43) ◽  
pp. 16803-16817 ◽  
Author(s):  
Michael J. Holliday ◽  
Ryan Ferrao ◽  
Gladys de Leon Boenig ◽  
Alberto Estevez ◽  
Elizabeth Helgason ◽  
...  
Keyword(s):  
Bound States ◽  
B Cell Lymphoma ◽  
Innate Immune ◽  
Mitogen Activated Protein Kinase ◽  
Ground State Structure ◽  
Caspase Recruitment Domain ◽  
Mitogen Activated Protein ◽  
Signaling Axis ◽  
Concomitant Reduction ◽  
The Stability

The caspase recruitment domain–containing protein 9 (CARD9)–B-cell lymphoma/leukemia 10 (Bcl10) signaling axis is activated in myeloid cells during the innate immune response to a variety of diverse pathogens. This signaling pathway requires a critical caspase recruitment domain (CARD)–CARD interaction between CARD9 and Bcl10 that promotes downstream activation of factors, including NF-κB and the mitogen-activated protein kinase (MAPK) p38. Despite these insights, CARD9 remains structurally uncharacterized, and little mechanistic understanding of its regulation exists. We unexpectedly found here that the CARD in CARD9 binds to Zn2+ with picomolar affinity—a concentration comparable with the levels of readily accessible Zn2+ in the cytosol. NMR solution structures of the CARD9–CARD in the apo and Zn2+-bound states revealed that Zn2+ has little effect on the ground-state structure of the CARD; yet the stability of the domain increased considerably upon Zn2+ binding, with a concomitant reduction in conformational flexibility. Moreover, Zn2+ binding inhibited polymerization of the CARD9–CARD into helical assemblies. Here, we also present a 20-Å resolution negative-stain EM (NS-EM) structure of these filamentous assemblies and show that they adopt a similar helical symmetry as reported previously for filaments of the Bcl10 CARD. Using both bulk assays and direct NS-EM visualization, we further show that the CARD9–CARD assemblies can directly template and thereby nucleate Bcl10 polymerization, a capacity considered critical to propagation of the CARD9–Bcl10 signaling cascade. Our findings indicate that CARD9 is a potential target of Zn2+-mediated signaling that affects Bcl10 polymerization in innate immune responses.

scholarly journals The chemotherapeutic agent DMXAA potently and specifically activates the TBK1–IRF-3 signaling axis

2007 ◽  
Vol 204 (7) ◽  
pp. 1559-1569 ◽  
Author(s):  
Zachary J. Roberts ◽  
Nadege Goutagny ◽  
Pin-Yu Perera ◽  
Hiroki Kato ◽  
Himanshu Kumar ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Fold Increase ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Advanced Phase ◽  
Novel Approach ◽  
Primary Mouse ◽  
Mouse Macrophages ◽  
Mitogen Activated Protein ◽  
Signaling Axis

Vascular disrupting agents (VDAs) represent a novel approach to the treatment of cancer, resulting in the collapse of tumor vasculature and tumor death. 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a VDA currently in advanced phase II clinical trials, yet its precise mechanism of action is unknown despite extensive preclinical and clinical investigations. Our data demonstrate that DMXAA is a novel and specific activator of the TANK-binding kinase 1 (TBK1)–interferon (IFN) regulatory factor 3 (IRF-3) signaling pathway. DMXAA treatment of primary mouse macrophages resulted in robust IRF-3 activation and ∼750-fold increase in IFN-β mRNA, and in contrast to the potent Toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS), signaling was independent of mitogen-activated protein kinase (MAPK) activation and elicited minimal nuclear factor κB–dependent gene expression. DMXAA-induced signaling was critically dependent on the IRF-3 kinase, TBK1, and IRF-3 but was myeloid differentiation factor 88–, Toll–interleukin 1 receptor domain–containing adaptor inducing IFN-β–, IFN promoter-stimulator 1–, and inhibitor of κB kinase–independent, thus excluding all known TLRs and cytosolic helicase receptors. DMXAA pretreatment of mouse macrophages induced a state of tolerance to LPS and vice versa. In contrast to LPS stimulation, DMXAA-induced IRF-3 dimerization and IFN-β expression were inhibited by salicylic acid. These findings detail a novel pathway for TBK1-mediated IRF-3 activation and provide new insights into the mechanism of this new class of chemotherapeutic drugs.

scholarly journals Anterograde trafficking of ciliary MAP kinase–like ICK/CILK1 by the intraflagellar transport machinery is required for intraciliary retrograde protein trafficking

2020 ◽  
Vol 295 (38) ◽  
pp. 13363-13376 ◽  
Author(s):  
Kentaro Nakamura ◽  
Tatsuro Noguchi ◽  
Mariko Takahara ◽  
Yoshihiro Omori ◽  
Takahisa Furukawa ◽  
...  
Keyword(s):  
Protein Trafficking ◽  
Intraflagellar Transport ◽  
Extracellular Vesicle ◽  
Mitogen Activated Protein Kinase ◽  
Ciliary Protein ◽  
Mitogen Activated Protein ◽  
Exogenous Expression ◽  
Bidirectional Movement ◽  
Dependent Transport ◽  
G Protein Coupled

ICK (also known as CILK1) is a mitogen-activated protein kinase–like kinase localized at the ciliary tip. Its deficiency is known to result in the elongation of cilia and causes ciliopathies in humans. However, little is known about how ICK is transported to the ciliary tip. We here show that the C-terminal noncatalytic region of ICK interacts with the intraflagellar transport (IFT)–B complex of the IFT machinery and participates in its transport to the ciliary tip. Furthermore, total internal reflection fluorescence microscopy demonstrated that ICK undergoes bidirectional movement within cilia, similarly to IFT particles. Analysis of ICK knockout cells demonstrated that ICK deficiency severely impairs the retrograde trafficking of IFT particles and ciliary G protein–coupled receptors. In addition, we found that in ICK knockout cells, ciliary proteins are accumulated at the bulged ciliary tip, which appeared to be torn off and released into the environment as an extracellular vesicle. The exogenous expression of various ICK constructs in ICK knockout cells indicated that the IFT-dependent transport of ICK, as well as its kinase activity and phosphorylation at the canonical TDY motif, is essential for ICK function. Thus, we unequivocally show that ICK transported to the ciliary tip is required for retrograde ciliary protein trafficking and consequently for normal ciliary function.

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