Mitochondrial p32/C1qbp Is a Critical Regulator of Dendritic Cell Metabolism and Maturation

Gotoh, Kazuhito; Morisaki, Takafumi; Setoyama, Daiki; Sasaki, Katsuhiko; Yagi, Minoru; Igami, Ko; Mizuguchi, Soichi; Uchiumi, Takeshi; Fukui, Yoshihiro; Kang, Dongchon

doi:10.1016/j.celrep.2018.10.057

Cited by 51 publications

(48 citation statements)

References 64 publications

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“…Complement component C1q subcomponent-binding protein (c1qbp), a multifunctional chaperone protein, plays an important role in mitochondrial function and supports mitochondrial metabolism and DC maturation. The production of citrate regulates DC maturity via c1qbp-dependent pyruvate dehydrogenase activity ( 120 ). 2-deoxyglucose impairs glycolysis in DC, which contributes to the decreased expression of CD40, CD86, and MHC-II and production of IL-6, IL-12p70, and TNF and causes a Tol-DC phenotype ( 119 ).…”

Section: The Metabolism Modification Of Tol-dcmentioning

confidence: 99%

Tolerogenic Dendritic Cells: The Pearl of Immunotherapy in Organ Transplantation

et al. 2020

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Over a half century, organ transplantation has become an effective method for the treatment of end-stage visceral diseases. Although the application of immunosuppressants (IS) minimizes the rate of allograft rejection, the common use of IS bring many adverse effects to transplant patients. Moreover, true transplant tolerance is very rare in clinical practice. Dendritic cells (DCs) are thought to be the most potent antigen-presenting cells, which makes a bridge between innate and adaptive immunity. Among their subsets, a small portion of DCs with immunoregulatory function was known as tolerogenic DC (Tol-DC). Previous reports demonstrated the ability of adoptively transferred Tol-DC to approach transplant tolerance in animal models. In this study, we summarized the properties, ex vivo generation, metabolism, and clinical attempts of Tol-DC. Tol-DC is expected to become a substitute for IS to enable patients to achieve immune tolerance in the future.

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Section: The Metabolism Modification Of Tol-dcmentioning

confidence: 99%

Tolerogenic Dendritic Cells: The Pearl of Immunotherapy in Organ Transplantation

et al. 2020

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“…Typically, catabolic metabolism in resting DCs is characterized by oxidative phosphorylation (OXPHOS) fueled by fatty acid oxidation (FAO) and limited glycolysis (Krawczyk et al, 2010, Gotoh et al, 2018, Zuo and Wan, 2019. During early DC activation by TLR agonists, DCs augment both aerobic glycolysis and OXPHOS to support the anabolic demands required for expansion of the ER and Golgi apparatus, de novo fatty acid (FA) synthesis, and production of inflammatory cytokines.…”

Section: Adj Enhances Cross-presentation Without Glycolytic Reprogrammentioning

confidence: 99%

Carbomer-based Nano-Emulsion Adjuvant Enhances Dendritic Cell Cross-presentation via Lipid Body Formation Independent of Glycolysis

Suresh

Lee

Kingstad-Bakke

et al. 2020

Preprint

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ADJ induces inflammasome activation in DCs, but deficiency for NLRP3, ASC or caspase 1 did not affect ADJ-mediated cross-presentationNext, we examined the effects of ADJ on the expression profiles of cytokines, chemokines and canonical cell surface markers of DC activation. Compared to untreated DCs, ADJ-treated DCs showed statistically significant, yet modest increases in expression of CD40, CD80, and CD86; no significant differences in expression were observed for MHC-I, MHC-II, or CCR7 (Fig. 1C).ADJ-treated DCs produced higher levels of IL-12 (p70), TNF-, IL-1, CCL3, CCL4, CXCL1, and RANTES, as compared to untreated DCs; no significant differences in expression were observed for IL-6, IL-10, and IFN- (Fig. 1D). Particularly, ADJ-stimulated DCs also produced significantly elevated levels of IL-1 and IL-18 (Fig. 1D), which is suggestive of inflammasome activation. Since inflammasome activation has been implicated in modulation of antigen presentation by DCs (Sokolovska et al., 2013, Li et al., 2019, we performed B3Z assays using DCs deficient in NLRP3, ASC, or caspase 1 to interrogate whether inflammasome activation is required for ADJ-induced cross-presentation in BMDCs. Surprisingly, loss of NLRP3, ASC or caspase 1 activity did not affect ADJ-induced cross-presentation by DCs, in vitro (Fig. 1E). To validate whether caspase 1 is required for cross-presentation in vivo, we immunized cohorts of wild type (WT) and caspase 1-deficient mice with ADJ+OVA, and quantified OVA SIINFEKLspecific CD8 T cells in spleens using MHC I tetramers at day 8 after immunization. Consistent with our results from B3Z assays, caspase 1 deficiency did not significantly affect the activation of SIINFEKL-specific CD8 T cells in spleens (Fig. 1F), suggesting that caspase 1 is not essential for ADJ-driven cross-presentation to CD8 T cells in vivo.

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“…vacuole and mitochondria suggest that E could actively participate in recruiting membranes and lipid processing machineries at the virion assembly site to provide suitable lipids for viral particle assembly. Amongst 226 identified proteins, BioID revealed high confidence interactions between E and: C1QBP (coagulation 102 , inflammation103 , infection and apoptotic processes 104 ), TMEM59 (autophagy 105 ), TMEM9B (enhances TNF, IL-1B, IL-6 and TLR ligand production; involved in NFB and MAPK pathways activation42 ),…”

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confidence: 99%

Global BioID-based SARS-CoV-2 proteins proximal interactome unveils novel ties between viral polypeptides and host factors involved in multiple COVID19-associated mechanisms

Laurent

Sofianatos

Komarova

et al. 2020

Preprint

128

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The worldwide SARS-CoV-2 outbreak poses a serious challenge to human societies and economies. SARS-CoV-2 proteins orchestrate complex pathogenic mechanisms that underlie COVID-19 disease. Thus, understanding how viral polypeptides rewire host protein networks enables better-founded therapeutic research. In complement to existing proteomic studies, in this study we define the first proximal interaction network of SARS-CoV-2 proteins, at the whole proteome level in human cells. Applying a proximity-dependent biotinylation (BioID)-based approach greatly expanded the current knowledge by detecting interactions within poorly soluble compartments, transient, and/or of weak affinity in living cells. Our BioID study was complemented by a stringent filtering and uncovered 2,128 unique cellular targets (1,717 not previously associated with SARS-CoV-1 or 2 proteins) connected to the N- and C-ter BioID-tagged 28 SARS-CoV-2 proteins by a total of 5,415 (5,236 new) proximal interactions. In order to facilitate data exploitation, an innovative interactive 3D web interface was developed to allow customized analysis and exploration of the landscape of interactions (accessible at http://www.sars-cov-2-interactome.org/). Interestingly, 342 membrane proteins including interferon and interleukin pathways factors, were associated with specific viral proteins. We uncovered ORF7a and ORF7b protein proximal partners that could be related to anosmia and ageusia symptoms. Moreover, comparing proximal interactomes in basal and infection-mimicking conditions (poly(I:C) treatment) allowed us to detect novel links with major antiviral response pathway components, such as ORF9b with MAVS and ISG20; N with PKR and TARB2; NSP2 with RIG-I and STAT1; NSP16 with PARP9-DTX3L. Altogether, our study provides an unprecedented comprehensive resource for understanding how SARS-CoV-2 proteins orchestrate host proteome remodeling and innate immune response evasion, which can inform development of targeted therapeutic strategies.

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Mitochondrial p32/C1qbp Is a Critical Regulator of Dendritic Cell Metabolism and Maturation

Abstract: Highlights d Mitochondrial p32 is an important factor for mitochondrial metabolism in DCs d p32 selectively supports DC maturation via PDH activity d p32 and PDH activity are necessary for DC maturation in vivo

Cited by 51 publications

References 64 publications

Tolerogenic Dendritic Cells: The Pearl of Immunotherapy in Organ Transplantation

Tolerogenic Dendritic Cells: The Pearl of Immunotherapy in Organ Transplantation

Carbomer-based Nano-Emulsion Adjuvant Enhances Dendritic Cell Cross-presentation via Lipid Body Formation Independent of Glycolysis

Global BioID-based SARS-CoV-2 proteins proximal interactome unveils novel ties between viral polypeptides and host factors involved in multiple COVID19-associated mechanisms

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