Forkhead box P3 positive (Foxp3(+)) regulatory T (Treg) cells suppress immune responses and regulate peripheral tolerance. Here we show that the atypical inhibitor of NFκB (IκB) IκB(NS) drives Foxp3 expression via association with the promoter and the conserved noncoding sequence 3 (CNS3) of the Foxp3 locus. Consequently, IκB(NS) deficiency leads to a substantial reduction of Foxp3(+) Treg cells in vivo and impaired Foxp3 induction upon transforming growth factor-β (TGF-β) treatment in vitro. Moreover, fewer Foxp3(+) Treg cells developed from IκB(NS)-deficient CD25(-)CD4(+) T cells adoptively transferred into immunodeficient recipients. Importantly, IκB(NS) was required for the transition of immature GITR(+)CD25(+)Foxp3(-) thymic Treg cell precursors into Foxp3(+) cells. In contrast to mice lacking c-Rel or Carma1, IκB(NS)-deficient mice do not show reduced Treg precursor cells. Our results demonstrate that IκB(NS) critically regulates Treg cell development in the thymus and during gut inflammation, indicating that strategies targeting IκB(NS) could modulate the Treg cell compartment.
Autophagy is a lysosomal degradation pathway important for cellular homeostasis, mammalian development, cancer and immunity. Many molecular components of autophagy have been identified, but little is known about regulatory mechanisms controlling their effector functions. Here, we show that, in contrast to other p38 MAP kinase activators, the growth arrest and DNA damage 45 beta (Gadd45b)-MAPK/ERK kinase kinase 4 (MEKK4) pathway specifically directs p38 to autophagosomes. This process results in an accumulation of autophagosomes through p38-mediated inhibition of lysosome fusion. Conversely, autophagic flux is increased in p38-deficient fibroblasts and Gadd45b-deficient cells. We further identified the underlying mechanism and demonstrate that phosphorylation of the autophagy regulator autophagy-related (Atg)5 at threonine 75 through p38 is responsible for inhibition of starvation-induced autophagy. Thus, we show for the first time that Atg5 activity is controlled by phosphorylation and, moreover, that the spatial regulation of p38 by Gadd45b/MEKK4 negatively regulates the autophagic process. Macroautophagy (hereafter referred to as autophagy) is a catabolic process, by which the cell degrades cytosolic content to supply metabolic processes with nutrients in order to maintain ATP production and macromolecular synthesis. Thus, autophagy acts as an efficient recycling mechanism in eukaryotic cells.1 Cellular stress, for example, nutrient deprivation, enhances autophagy as a survival mechanism during starvation. In addition, autophagy serves important functions in development, cancer, cell death and immunity in mammals. 1,2 Autophagy is controlled by conserved key regulators known as autophagy-related (Atg) proteins.3 At the onset of the autophagy cascade, Atg6/Beclin-1 forms a complex with the class III phosphatidylinoside kinase Vps34, which induces expansion of the precursor membrane vesicle, the phagophore, via recruitment of additional Atg proteins. During expansion, the double membrane vesicle surrounds cytosolic content, and the completed vesicle, called autophagosome, finally fuses with lysosomes to degrade the autophagosomal content.3 Maturation of autophagosomes is regulated by two ubiquitin-like conjugation systems, namely the Atg8-phosphatidylethanolamine (PE) and the Atg5-12/16L1 conjugation system. The Atg5-Atg12 conjugate interacts with Atg16L1, which tethers the complex to phagophores and autophagosomes. This complex then acts as an E3-like ubiquitin ligase for microtubule-associated protein 1 light chain 3 (LC3) lipidation. The conversion of LC3 to the PE-conjugated LC3-II form and its recruitment to the membrane serves as a wellaccepted marker for autophagy.Although Atg5-independent autophagy has been described, 4 Atg5 is crucial for autophagy under most circumstances and Atg5-deficient mouse embryonic fibroblasts (MEFs) lack LC3 conversion and autophagy. Therefore, Atg5-deficient mice die postnatal owing to their inability to cope with starvation during the neonatal period. 5 In addition, Atg5 see...
Nuclear factor κB (NF-κB) controls a multitude of physiological processes such as cell differentiation, cytokine expression, survival and proliferation. Since NF-κB governs embryogenesis, tissue homeostasis and the functions of innate and adaptive immune cells it represents one of the most important and versatile signaling networks known. Its activity is regulated via the inhibitors of NF-κB signaling, the IκB proteins. Classical IκBs, like the prototypical protein IκBα, sequester NF-κB transcription factors in the cytoplasm by masking of their nuclear localization signals (NLS). Thus, binding of NF-κB to the DNA is inhibited. The accessibility of the NLS is controlled via the degradation of IκBα. Phosphorylation of the conserved serine residues 32 and 36 leads to polyubiquitination and subsequent proteasomal degradation. This process marks the central event of canonical NF-κB activation. Once their NLS is accessible, NF-κB transcription factors translocate into the nucleus, bind to the DNA and regulate the transcription of their respective target genes. Several studies described a distinct group of atypical IκB proteins, referred to as the BCL-3 subfamily. Those atypical IκBs show entirely different sub-cellular localizations, activation kinetics and an unexpected functional diversity. First of all, their interaction with NF-κB transcription factors takes place in the nucleus in contrast to classical IκBs, whose binding to NF-κB predominantly occurs in the cytoplasm. Secondly, atypical IκBs are strongly induced after NF-κB activation, for example by LPS and IL-1β stimulation or triggering of B cell and T cell antigen receptors, but are not degraded in the first place like their conventional relatives. Finally, the interaction of atypical IκBs with DNA-associated NF-κB transcription factors can further enhance or diminish their transcriptional activity. Thus, they do not exclusively act as inhibitors of NF-κB activity. The capacity to modulate NF-κB transcription either positively or negatively, represents their most important and unique mechanistic difference to classical IκBs. Several reports revealed the importance of atypical IκB proteins for immune homeostasis and the severe consequences following their loss of function. This review summarizes insights into the physiological processes regulated by this protein class and the relevance of atypical IκB functioning.
Autophagy is a vital catabolic process for degrading bulky cytosolic contents, which cannot be resorbed via the proteasome. First described as a survival mechanism during nutrient starvation conditions, recent reports have demonstrated that autophagy supports metabolic functions of T cells at various stages of maturation and effector function. Autophagy is crucial for T-cell development at the precursor stage as self-renewability and quiescence of hematopoietic stem cells depend on autophagy of the mitochondria and the endoplasmic reticulum. Later, during development in the thymus, autophagy regulates peptide presentation in stromal cells and professional antigen-presenting cells, which mediate thymocyte selection. Furthermore, the metabolic changes when mature T cells enter the periphery and when they are activated are both dependent on autophagy. Lastly, autophagy prevents early aging and, thus, ensures maintenance of memory T cells. Autophagy is an eukaryotic, cytoplasmic (self-)recycling process, in which proteins as well as entire organelles are degraded via lysosomes. There are three different types of autophagy, namely chaperonemediated autophagy, microautophagy and macroautophagy. Chaperone-mediated autophagy, unlike the other two types of autophagy, only degrades soluble cytosolic proteins by directly transferring heat-shock cognate protein of 70 kDa-tagged proteins across the lysosomal membrane. 1 Both micro-and macroautophagy can be nonselective as well as specific in their cargo selection and both are capable of degrading large-sized molecules. During microautophagy, the lysosomal membrane invaginates to sequester cytosolic content directly. 2 Macroautophagy is distinct, in that a doublemembrane structure, the autophagosome, is formed around its cytosolic cargo. This is also the most well-studied type of autophagy, and as this review deals with macroautophagy, it will be referred to simply as 'autophagy' hereafter.Autophagy is essential for degradation of aggregated proteins (aggrephagy) 3 and damaged organelles including mitochondria (mitophagy), peroxisomes (pexophagy) and ER (ERphagy). These were previously reviewed in Ding and Yin, 4 Sakai et al. 5 and Bernales et al., 6 respectively. As autophagy is a fundamental process needed by almost all cell types to maintain cell homeostasis, a basal level of autophagy occurs constantly. 7 Beyond this, autophagy is vital for cells during stress conditions such as starvation, activation, growth and proliferation, to provide cells with essential metabolic intermediates. These basic autophagic functions are relevant in diseases as well as aging, as the accumulation of aggregated proteins, damaged organelles or other molecules is an underlying problem of many diseases. For instance, autophagy has been implicated in neurodegenerative diseases, 8,9 Crohn's disease, 10,11 cancer, 12,13 aging 4,15 and cystic fibrosis, 16 as well as metabolic-related diseases such as fatty liver (macrolipophagy), 17 autophagic vacuolar myopathies (glycogen degradation) 18,19 and di...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.