Behind the Scenes: Nod-Like Receptor X1 Controls Inflammation and Metabolism

Snäkä, Tiia

doi:10.3389/fcimb.2020.609812

Cited by 17 publications

(7 citation statements)

References 74 publications

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“…In parallel, it is important to perform mobilization studies in these mice and to assess the effect of another paralog, Nlrp1a , in HSPC mobilization and homing. It is known that various members of the NOD-like family of receptors have different biological effects, and some promote, while others inhibit, inflammation [ 84 , 85 ]. These inhibitory NOD-like receptors, for example, NLRP12, NLRC3, and NLRX1, attenuate diverse signaling pathways involving NF-κB and type I interferon (IFN) signaling, together with cellular processes such as generation of reactive oxygen species (ROS) and autophagy [ 83 – 85 ].…”

Section: Introductionmentioning

confidence: 99%

Hematopoiesis and innate immunity: an inseparable couple for good and bad times, bound together by an hormetic relationship

Ratajczak

Kucia

2021

Leukemia

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Hematopoietic and immune cells originate from a common hematopoietic/lymphopoietic stem cell what explains that these different cell types often share the same receptors and respond to similar factors. Moreover, the common goal of both lineages is to ensure tissue homeostasis under steady-state conditions, fight invading pathogens, and promote tissue repair. We will highlight accumulating evidence that innate and adaptive immunity modulate several aspects of hematopoiesis within the hormetic zone in which the biological response to low exposure to potential stressors generally is favorable and benefits hematopoietic stem/progenitor cells (HSPCs). Innate immunity impact on hematopoiesis is pleiotropic and involves both the cellular arm, comprised of innate immunity cells, and the soluble arm, whose major component is the complement cascade (ComC). In addition, several mediators released by innate immunity cells, including inflammatory cytokines and small antimicrobial cationic peptides, affect hematopoiesis. There are intriguing observations that HSPCs and immune cells share several cell-surface pattern-recognition receptors (PRRs), such as Toll-like receptors (TLRs) and cytosol-expressed NOD, NOD-like, and RIG-I-like receptors and thus can be considered “pathogen sensors”. In addition, not only lymphocytes but also HSPCs express functional intracellular complement proteins, defined as complosome which poses challenging questions for further investigation of the intracellular ComC-mediated intracrine regulation of hematopoiesis.

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Section: Introductionmentioning

confidence: 99%

Hematopoiesis and innate immunity: an inseparable couple for good and bad times, bound together by an hormetic relationship

Ratajczak

Kucia

2021

Leukemia

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“…Cytosolic pathogens, such as Rickettsia, have evolved to evade the host cytosolic antimicrobial processes (71,72). Modulation of host metabolism is a general common theme among intracellular pathogens, leading to a suitable nutritional niche for pathogen proliferation, and that has been well characterized for Mycobacterium (52,65,66,(73)(74)(75). For intravacuolar pathogens, the crux of these host processes is evasion of the endosomal-lysosomal degradation pathway by most intravacuolar pathogens, such as Mycobacterium, Chlamydia, and Salmonella (1, 2).…”

Section: Discussionmentioning

confidence: 99%

An Indispensable Role for the MavE Effector of Legionella pneumophila in Lysosomal Evasion

Vaughn

Voth

Price

et al. 2021

mBio

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Diversion of the Legionella pneumophila-containing vacuole (LCV) from the host endosomal-lysosomal degradation pathway is one of the main virulence features essential for manifestation of Legionnaires’ pneumonia. Many of the ∼350 Dot/Icm-injected effectors identified in L. pneumophila have been shown to interfere with various host pathways and processes, but no L. pneumophila effector has ever been identified to be indispensable for lysosomal evasion. While most single effector mutants of L. pneumophila do not exhibit a defective phenotype within macrophages, we show that the MavE effector is essential for intracellular growth of L. pneumophila in human monocyte-derived macrophages (hMDMs) and amoebae and for intrapulmonary proliferation in mice. The mavE null mutant fails to remodel the LCV with endoplasmic reticulum (ER)-derived vesicles and is trafficked to the lysosomes where it is degraded, similar to formalin-killed bacteria. During infection of hMDMs, the MavE effector localizes to the poles of the LCV membrane. The crystal structure of MavE, resolved to 1.8 Å, reveals a C-terminal transmembrane helix, three copies of tyrosine-based sorting motifs, and an NPxY eukaryotic motif, which binds phosphotyrosine-binding domains present on signaling and adaptor eukaryotic proteins. Two point mutations within the NPxY motif result in attenuation of L. pneumophila in both hMDMs and amoeba. The substitution defects of P78 and D64 are associated with failure of vacuoles harboring the mutant to be remodeled by the ER and results in fusion of the vacuole to the lysosomes leading to bacterial degradation. Therefore, the MavE effector of L. pneumophila is indispensable for phagosome biogenesis and lysosomal evasion. IMPORTANCE Intracellular proliferation of Legionella pneumophila within a vacuole in human alveolar macrophages is essential for manifestation of Legionnaires’ pneumonia. Intravacuolar growth of the pathogen is totally dependent on remodeling the L. pneumophila-containing vacuole (LCV) by the ER and on its evasion of the endosomal-lysosomal degradation pathway. The pathogen has evolved to inject ∼350 protein effectors into the host cell where they modulate various host processes, but no L. pneumophila effector has ever been identified to be indispensable for lysosomal evasion. We show that the MavE effector localizes to the poles of the LCV membrane and is essential for lysosomal evasion and intracellular growth of L. pneumophila and for intrapulmonary proliferation in mice. The crystal structure of MavE shows an NPxY eukaryotic motif essential for ER-mediated remodeling and lysosomal evasion by the LCV. Therefore, the MavE effector of L. pneumophila is indispensable for phagosome biogenesis and lysosomal evasion.

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“…NLRs are considered regulators of tumorigenesis, cancer cell stemness and chemoresistance. The inappropriate activation of NLRs modulates the tissue microenvironment and potentiates the risk for cancers [ 27 , 28 ]. TNF signaling leads to cell survival, proliferation and differentiation.…”

Section: Discussionmentioning

confidence: 99%

Quantitative phosphoproteomic analysis reveals chemoresistance-related proteins and signaling pathways induced by rhIL-6 in human osteosarcoma cells

Zhang

Wang

et al. 2021

Cancer Cell Int

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Background IL-6 plays a pivotal role in resistance to chemotherapeutics, including lobaplatin. However, the underlying mechanisms are still unclear. This study was to investigate the changes in phosphoproteins and their related signaling pathways in the process of IL-6-induced chemoresistance to lobaplain in osteosarcoma cells. Methods We performed a quantitative phosphoproteomic analysis of the response of SaOS-2 osteosarcoma cells to recombinant human IL-6 (rhIL-6) intervention prior to lobaplatin treatment. The cells were divided into the control group (Con), the lobaplatin group (Lob), and the rhIL-6-and-lobaplatin group (IL-6). Three biological replicates of each group were included. The differentially expressed phosphoproteins were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Netphos 3.1 was used for the prediction of kinases, and STRING was used for the visualization of protein–protein interactions. The conserved motifs surrounding the phosphorylated residues were analyzed using the motif-x algorithm. Western blot analysis was performed to verify the differential expression of p-FLNC, its predicted kinase and the related signaling pathway. The results of the bioinformatic analysis were validated by immunohistochemical staining of clinical specimens. Results In total, 3373 proteins and 12,183 peptides, including 3232 phosphorylated proteins and 11,358 phosphorylated peptides, were identified and quantified. Twenty-three significantly differentially expressed phosphoproteins were identified in the comparison between the IL-6 and Lob groups, and p-FLNC ranked second among these phosphoproteins. GO and KEGG analyses revealed the pivotal role of mitogen-activated protein kinase signaling in drug resistance induced by rhIL-6. Four motifs, namely, -SPxxK-, -RxxSP-, -SP-, and -SPK-, demonstrated higher expression in the IL-6 group than in the Lob group. The western blot analysis results verified the higher expression of p-FLNC, AKT1, and p-ERK and the lower expression of p-JNK in the IL-6 group than in the Con and Lob groups. The immunohistochemical staining results showed that p-FLNC, AKT1 and p-ERK1/2 were highly expressed in platinum-resistant clinical specimens but weakly expressed in platinum-sensitive specimens, and platinum-resistant osteosarcoma specimens demonstrated weak expression of p-JNK. Conclusions This phosphoproteomic study is the first to reveal the signature associated with rhIL-6 intervention before lobaplatin treatment in human osteosarcoma cells. p-FLNC, AKT1, and MAPK signaling contributes to resistance to lobaplatin in osteosarcoma SaOS-2 cells and may represent molecular targets to overcome osteosarcoma chemoresistance.

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Behind the Scenes: Nod-Like Receptor X1 Controls Inflammation and Metabolism

Cited by 17 publications

References 74 publications

Hematopoiesis and innate immunity: an inseparable couple for good and bad times, bound together by an hormetic relationship

Hematopoiesis and innate immunity: an inseparable couple for good and bad times, bound together by an hormetic relationship

An Indispensable Role for the MavE Effector of Legionella pneumophila in Lysosomal Evasion

Quantitative phosphoproteomic analysis reveals chemoresistance-related proteins and signaling pathways induced by rhIL-6 in human osteosarcoma cells

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