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Biochimica Et Biophysica Acta.... May 2018Nrf2 and its endogenous inhibitor, Keap1, function as a ubiquitous, evolutionarily conserved intracellular defense mechanism to counteract oxidative stress. Sequestered... (Review)
Review
Nrf2 and its endogenous inhibitor, Keap1, function as a ubiquitous, evolutionarily conserved intracellular defense mechanism to counteract oxidative stress. Sequestered by cytoplasmic Keap1 and targeted to proteasomal degradation in basal conditions, in case of oxidative stress Nrf2 detaches from Keap1 and translocates to the nucleus, where it heterodimerizes with one of the small Maf proteins. The heterodimers recognize the AREs, that are enhancer sequences present in the regulatory regions of Nrf2 target genes, essential for the recruitment of key factors for transcription. In the present review we briefly introduce the Nrf2-Keap1 system and describe Nrf2 functions, illustrate the Nrf2-NF-κB cross-talk, and highlight the effects of the Nrf2-Keap1 system in the physiology and pathophysiology of striated muscle tissue taking into account its role(s) in oxidative stress and reductive stress.
Topics: Cell Nucleus; Humans; Kelch-Like ECH-Associated Protein 1; Maf Transcription Factors; NF-E2-Related Factor 2; NF-kappa B; Oxidation-Reduction; Oxidative Stress; Signal Transduction
PubMed: 29499228
DOI: 10.1016/j.bbamcr.2018.02.010 -
Physiological Reviews Jul 2018The Kelch-like ECH-associated protein 1-NF-E2-related factor 2 (KEAP1-NRF2) system forms the major node of cellular and organismal defense against oxidative and... (Review)
Review
The Kelch-like ECH-associated protein 1-NF-E2-related factor 2 (KEAP1-NRF2) system forms the major node of cellular and organismal defense against oxidative and electrophilic stresses of both exogenous and endogenous origins. KEAP1 acts as a cysteine thiol-rich sensor of redox insults, whereas NRF2 is a transcription factor that robustly transduces chemical signals to regulate a battery of cytoprotective genes. KEAP1 represses NRF2 activity under quiescent conditions, whereas NRF2 is liberated from KEAP1-mediated repression on exposure to stresses. The rapid inducibility of a response based on a derepression mechanism is an important feature of the KEAP1-NRF2 system. Recent studies have unveiled the complexities of the functional contributions of the KEAP1-NRF2 system and defined its broader involvement in biological processes, including cell proliferation and differentiation, as well as cytoprotection. In this review, we describe historical milestones in the initial characterization of the KEAP1-NRF2 system and provide a comprehensive overview of the molecular mechanisms governing the functions of KEAP1 and NRF2, as well as their roles in physiology and pathology. We also refer to the clinical significance of the KEAP1-NRF2 system as an important prophylactic and therapeutic target for various diseases, particularly aging-related disorders. We believe that controlled harnessing of the KEAP1-NRF2 system is a key to healthy aging and well-being in humans.
Topics: Amino Acid Sequence; Carcinogenesis; Cytoprotection; Gene Expression Regulation; Homeostasis; Humans; Inflammation; Kelch-Like ECH-Associated Protein 1; Maf Transcription Factors; NF-E2-Related Factor 2; Oxidation-Reduction
PubMed: 29717933
DOI: 10.1152/physrev.00023.2017 -
Nature Jun 2018The expression of co-inhibitory receptors, such as CTLA-4 and PD-1, on effector T cells is a key mechanism for ensuring immune homeostasis. Dysregulated expression of...
The expression of co-inhibitory receptors, such as CTLA-4 and PD-1, on effector T cells is a key mechanism for ensuring immune homeostasis. Dysregulated expression of co-inhibitory receptors on CD4 T cells promotes autoimmunity, whereas sustained overexpression on CD8 T cells promotes T cell dysfunction or exhaustion, leading to impaired ability to clear chronic viral infections and diseases such as cancer. Here, using RNA and protein expression profiling at single-cell resolution in mouse cells, we identify a module of co-inhibitory receptors that includes not only several known co-inhibitory receptors (PD-1, TIM-3, LAG-3 and TIGIT) but also many new surface receptors. We functionally validated two new co-inhibitory receptors, activated protein C receptor (PROCR) and podoplanin (PDPN). The module of co-inhibitory receptors is co-expressed in both CD4 and CD8 T cells and is part of a larger co-inhibitory gene program that is shared by non-responsive T cells in several physiological contexts and is driven by the immunoregulatory cytokine IL-27. Computational analysis identified the transcription factors PRDM1 and c-MAF as cooperative regulators of the co-inhibitory module, and this was validated experimentally. This molecular circuit underlies the co-expression of co-inhibitory receptors in T cells and identifies regulators of T cell function with the potential to control autoimmunity and tumour immunity.
Topics: Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Female; Gene Regulatory Networks; Immune Tolerance; Interleukin-27; Lymphocytes, Tumor-Infiltrating; Male; Melanoma; Mice; Mice, Inbred C57BL; Mice, Knockout; Positive Regulatory Domain I-Binding Factor 1; Proto-Oncogene Proteins c-maf; Receptors, Cell Surface; Reproducibility of Results; Transcription, Genetic
PubMed: 29899446
DOI: 10.1038/s41586-018-0206-z -
Science (New York, N.Y.) Dec 2023Skin-resident CD8 T cells include distinct interferon-γ-producing [tissue-resident memory T type 1 (T1)] and interleukin-17 (IL-17)-producing (T17) subsets that...
Skin-resident CD8 T cells include distinct interferon-γ-producing [tissue-resident memory T type 1 (T1)] and interleukin-17 (IL-17)-producing (T17) subsets that differentially contribute to immune responses. However, whether these populations use common mechanisms to establish tissue residence is unknown. In this work, we show that T1 and T17 cells navigate divergent trajectories to acquire tissue residency in the skin. T1 cells depend on a T-bet-Hobit-IL-15 axis, whereas T17 cells develop independently of these factors. Instead, c-Maf commands a tissue-resident program in T17 cells parallel to that induced by Hobit in T1 cells, with an ICOS-c-Maf-IL-7 axis pivotal to T17 cell commitment. Accordingly, by targeting this pathway, skin T17 cells can be ablated without compromising their T1 counterparts. Thus, skin-resident T cells rely on distinct molecular circuitries, which can be exploited to strategically modulate local immunity.
Topics: CD8-Positive T-Lymphocytes; Immunologic Memory; Memory T Cells; Skin; Humans; Th17 Cells; Inducible T-Cell Co-Stimulator Ligand; Proto-Oncogene Proteins c-maf; Interleukin-7
PubMed: 38033053
DOI: 10.1126/science.adi8885 -
Cell Stem Cell Apr 2022The liver vascular network is patterned by sinusoidal and hepatocyte co-zonation. How intra-liver vessels acquire their hierarchical specialized functions is unknown. We...
The liver vascular network is patterned by sinusoidal and hepatocyte co-zonation. How intra-liver vessels acquire their hierarchical specialized functions is unknown. We study heterogeneity of hepatic vascular cells during mouse development through functional and single-cell RNA-sequencing. The acquisition of sinusoidal endothelial cell identity is initiated during early development and completed postnatally, originating from a pool of undifferentiated vascular progenitors at E12. The peri-natal induction of the transcription factor c-Maf is a critical switch for the sinusoidal identity determination. Endothelium-restricted deletion of c-Maf disrupts liver sinusoidal development, aberrantly expands postnatal liver hematopoiesis, promotes excessive postnatal sinusoidal proliferation, and aggravates liver pro-fibrotic sensitivity to chemical insult. Enforced c-Maf overexpression in generic human endothelial cells switches on a liver sinusoidal transcriptional program that maintains hepatocyte function. c-Maf represents an inducible intra-organotypic and niche-responsive molecular determinant of hepatic sinusoidal cell identity and lays the foundation for the strategies for vasculature-driven liver repair.
Topics: Animals; Capillaries; Endothelial Cells; Endothelium; Liver; Liver Cirrhosis; Liver Regeneration; Mice; Proto-Oncogene Proteins c-maf
PubMed: 35364013
DOI: 10.1016/j.stem.2022.03.002 -
Nature Feb 2018Both microbial and host genetic factors contribute to the pathogenesis of autoimmune diseases. There is accumulating evidence that microbial species that potentiate...
Both microbial and host genetic factors contribute to the pathogenesis of autoimmune diseases. There is accumulating evidence that microbial species that potentiate chronic inflammation, as in inflammatory bowel disease, often also colonize healthy individuals. These microorganisms, including the Helicobacter species, can induce pathogenic T cells and are collectively referred to as pathobionts. However, how such T cells are constrained in healthy individuals is not yet understood. Here we report that host tolerance to a potentially pathogenic bacterium, Helicobacter hepaticus, is mediated by the induction of RORγtFOXP3 regulatory T (iT) cells that selectively restrain pro-inflammatory T helper 17 (T17) cells and whose function is dependent on the transcription factor c-MAF. Whereas colonization of wild-type mice by H. hepaticus promoted differentiation of RORγt-expressing microorganism-specific iT cells in the large intestine, in disease-susceptible IL-10-deficient mice, there was instead expansion of colitogenic T17 cells. Inactivation of c-MAF in the T cell compartment impaired differentiation and function, including IL-10 production, of bacteria-specific iT cells, and resulted in the accumulation of H. hepaticus-specific inflammatory T17 cells and spontaneous colitis. By contrast, RORγt inactivation in T cells had only a minor effect on the bacteria-specific T and T17 cell balance, and did not result in inflammation. Our results suggest that pathobiont-dependent inflammatory bowel disease is driven by microbiota-reactive T cells that have escaped this c-MAF-dependent mechanism of iT-T17 homeostasis.
Topics: Animals; Bioengineering; Colitis; Female; Forkhead Transcription Factors; Helicobacter hepaticus; Homeostasis; Host-Pathogen Interactions; Immune Tolerance; Interleukin-10; Intestines; Male; Mice; Nuclear Receptor Subfamily 1, Group F, Member 3; Proto-Oncogene Proteins c-maf; T-Lymphocytes, Regulatory; Th17 Cells
PubMed: 29414937
DOI: 10.1038/nature25500 -
Nature Immunology May 2023Resident tissue macrophages (RTMs) are differentiated immune cells that populate distinct niches and exert important tissue-supportive functions. RTM maintenance is...
Resident tissue macrophages (RTMs) are differentiated immune cells that populate distinct niches and exert important tissue-supportive functions. RTM maintenance is thought to rely either on differentiation from monocytes or on RTM self-renewal. Here, we used a mouse model of inducible lung interstitial macrophage (IM) niche depletion and refilling to investigate the development of IMs in vivo. Using time-course single-cell RNA-sequencing analyses, bone marrow chimeras and gene targeting, we found that engrafted Ly6C classical monocytes proliferated locally in a Csf1 receptor-dependent manner before differentiating into IMs. The transition from monocyte proliferation toward IM subset specification was controlled by the transcription factor MafB, while c-Maf specifically regulated the identity of the CD206 IM subset. Our data provide evidence that, in the mononuclear phagocyte system, the ability to proliferate is not merely restricted to myeloid progenitor cells and mature RTMs but is also a tightly regulated capability of monocytes developing into RTMs in vivo.
Topics: Animals; Mice; Monocytes; Macrophages; Cell Differentiation; Lung; Cell Proliferation; MafB Transcription Factor
PubMed: 36928411
DOI: 10.1038/s41590-023-01468-3 -
Nature Communications Jul 2021Hypoxia plays a critical role in tumor progression including invasion and metastasis. To determine critical genes regulated by hypoxia that promote invasion and...
Hypoxia plays a critical role in tumor progression including invasion and metastasis. To determine critical genes regulated by hypoxia that promote invasion and metastasis, we screen fifty hypoxia inducible genes for their effects on invasion. In this study, we identify v-maf musculoaponeurotic fibrosarcoma oncogene homolog F (MAFF) as a potent regulator of tumor invasion without affecting cell viability. MAFF expression is elevated in metastatic breast cancer patients and is specifically correlated with hypoxic tumors. Combined ChIP- and RNA-sequencing identifies IL11 as a direct transcriptional target of the heterodimer between MAFF and BACH1, which leads to activation of STAT3 signaling. Inhibition of IL11 results in similar levels of metastatic suppression as inhibition of MAFF. This study demonstrates the oncogenic role of MAFF as an activator of the IL11/STAT3 pathways in breast cancer.
Topics: Animals; Basic-Leucine Zipper Transcription Factors; Breast Neoplasms; Cell Hypoxia; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Interleukin-11; MafF Transcription Factor; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Nuclear Proteins; Prognosis; STAT3 Transcription Factor; Signal Transduction; Transcription, Genetic
PubMed: 34262028
DOI: 10.1038/s41467-021-24631-6 -
Science Immunology Oct 2021Macrophages are an essential part of tissue development and physiology. Perivascular macrophages have been described in tissues and appear to play a role in development...
Macrophages are an essential part of tissue development and physiology. Perivascular macrophages have been described in tissues and appear to play a role in development and disease processes, although it remains unclear what the key features of these cells are. Here, we identify a subpopulation of perivascular macrophages in several organs, characterized by their dependence on the transcription factor c-MAF and displaying nonconventional macrophage markers including LYVE1, folate receptor 2, and CD38. Conditional deletion of c-MAF in macrophage lineages caused ablation of perivascular macrophages in the brain and altered muscularis macrophages program in the intestine. In the white adipose tissue (WAT), c-MAF–deficient perivascular macrophages displayed an altered gene expression profile, which was linked to an increased vascular branching. Upon feeding high-fat diet (HFD), mice with c-MAF–deficient macrophages showed improved metabolic parameters compared with wild-type mice, including less weight gain, greater glucose tolerance, and reduced inflammatory cell profile in WAT. These results define c-MAF as a central regulator of the perivascular macrophage transcriptional program in vivo and reveal an important role for this tissue-resident macrophage population in the regulation of metabolic syndrome.
Topics: Adipose Tissue; Animals; Diet; Female; Humans; Macrophages; Male; Metabolic Syndrome; Mice; Mice, Inbred Strains; Proto-Oncogene Proteins c-maf
PubMed: 34597123
DOI: 10.1126/sciimmunol.abg7506 -
Blood Mar 2021The oncogenic transcription factor c-Maf has been proposed as an ideal therapeutic target for multiple myeloma (MM), but how to achieve it is still elusive. In the...
The oncogenic transcription factor c-Maf has been proposed as an ideal therapeutic target for multiple myeloma (MM), but how to achieve it is still elusive. In the present study, we found the Otub1/c-Maf axis could be a potential target. Otub1, an OTU family deubiquitinase, was found to interact with c-Maf by mass spectrometry. Otub1 abrogates c-Maf K48-linked polyubiquitination, thus preventing its degradation and enhancing its transcriptional activity. Specifically, this deubiquitinating activity depends on its Lys71 and the N terminus but is independent of UBE2O, a known E2 of c-Maf. Otub1 promotes MM cell survival and MM tumor growth. In contrast, silence of Otub1 leads to c-Maf degradation and c-Maf-expressing MM cell apoptosis. Therefore, the Otub1/c-Maf axis could be a therapeutic target of MM. In order to explore this concept, we performed a c-Maf recognition element-driven luciferase-based screen against US Food and Drug Administration-approved drugs and natural products, from which the generic cardiac glycoside lanatoside C (LanC) is found to prevent c-Maf deubiquitination and induces its degradation by disrupting the interaction of Otub1 and c-Maf. Consequently, LanC inhibits c-Maf transcriptional activity, induces c-Maf-expressing MM cell apoptosis, and suppresses MM growth and prolongs overall survival of model mice, but without apparent toxicity. Therefore, the present study identifies Otub1 as a novel deubiquitinase of c-Maf and establishes that the Otub1/c-Maf axis is a potential therapeutic target for MM.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Deubiquitinating Enzymes; Drug Discovery; HEK293 Cells; Humans; Mice, Inbred BALB C; Mice, Nude; Multiple Myeloma; Protein Interaction Maps; Proto-Oncogene Proteins c-maf; Signal Transduction; Ubiquitination; Mice
PubMed: 32842143
DOI: 10.1182/blood.2020005199