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Zinc finger proteins: insights into the transcriptional and post transcriptional regulation of immune response.
Rakhra, G, Rakhra, G
Molecular biology reports. 2021;(7):5735-5743
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Abstract
BACKGROUND Zinc finger proteins encompass one of the unique and large families of proteins with diversified biological functions in the human body. These proteins are primarily considered to be DNA binding transcription factors; however, owing to the diverse array of zinc-finger domains, they are able to interact with molecules other than DNA like RNA, proteins, lipids and PAR (poly-ADP-ribose). Evidences from recent scientific studies have provided an insight into the potential functions of zinc finger proteins in immune system regulation both at the transcriptional and post transcriptional level. However, the mechanism and importance of zinc finger proteins in the regulation of immune response is not very well defined and understood. This review highlights in detail the importance of zinc finger proteins in the regulation of immune system at transcriptional and post transcriptional level. CONCLUSION Different types of zinc finger proteins are involved in immune system regulation and their mechanism of regulation is discussed herewith.
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MiT Family Transcriptional Factors in Immune Cell Functions.
Kim, S, Song, HS, Yu, J, Kim, YM
Molecules and cells. 2021;(5):342-355
Abstract
The microphthalmia-associated transcription factor family (MiT family) proteins are evolutionarily conserved transcription factors that perform many essential biological functions. In mammals, the MiT family consists of MITF (microphthalmia-associated transcription factor or melanocyte-inducing transcription factor), TFEB (transcription factor EB), TFE3 (transcription factor E3), and TFEC (transcription factor EC). These transcriptional factors belong to the basic helix-loop-helix-leucine zipper (bHLH-LZ) transcription factor family and bind the E-box DNA motifs in the promoter regions of target genes to enhance transcription. The best studied functions of MiT proteins include lysosome biogenesis and autophagy induction. In addition, they modulate cellular metabolism, mitochondria dynamics, and various stress responses. The control of nuclear localization via phosphorylation and dephosphorylation serves as the primary regulatory mechanism for MiT family proteins, and several kinases and phosphatases have been identified to directly determine the transcriptional activities of MiT proteins. In different immune cell types, each MiT family member is shown to play distinct or redundant roles and we expect that there is far more to learn about their functions and regulatory mechanisms in host defense and inflammatory responses.
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LAG-3: from molecular functions to clinical applications.
Maruhashi, T, Sugiura, D, Okazaki, IM, Okazaki, T
Journal for immunotherapy of cancer. 2020;(2)
Abstract
To prevent the destruction of tissues owing to excessive and/or inappropriate immune responses, immune cells are under strict check by various regulatory mechanisms at multiple points. Inhibitory coreceptors, including programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4), serve as critical checkpoints in restricting immune responses against self-tissues and tumor cells. Immune checkpoint inhibitors that block PD-1 and CTLA-4 pathways significantly improved the outcomes of patients with diverse cancer types and have revolutionized cancer treatment. However, response rates to such therapies are rather limited, and immune-related adverse events are also observed in a substantial patient population, leading to the urgent need for novel therapeutics with higher efficacy and lower toxicity. In addition to PD-1 and CTLA-4, a variety of stimulatory and inhibitory coreceptors are involved in the regulation of T cell activation. Such coreceptors are listed as potential drug targets, and the competition to develop novel immunotherapies targeting these coreceptors has been very fierce. Among such coreceptors, lymphocyte activation gene-3 (LAG-3) is expected as the foremost target next to PD-1 in the development of cancer therapy, and multiple clinical trials testing the efficacy of LAG-3-targeted therapy are underway. LAG-3 is a type I transmembrane protein with structural similarities to CD4. Accumulating evidence indicates that LAG-3 is an inhibitory coreceptor and plays pivotal roles in autoimmunity, tumor immunity, and anti-infection immunity. In this review, we summarize the current understanding of LAG-3, ranging from its discovery to clinical application.
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Transcriptional Factors Regulate Plant Stress Responses through Mediating Secondary Metabolism.
Meraj, TA, Fu, J, Raza, MA, Zhu, C, Shen, Q, Xu, D, Wang, Q
Genes. 2020;(4)
Abstract
Plants are adapted to sense numerous stress stimuli and mount efficient defense responses by directing intricate signaling pathways. They respond to undesirable circumstances to produce stress-inducible phytochemicals that play indispensable roles in plant immunity. Extensive studies have been made to elucidate the underpinnings of defensive molecular mechanisms in various plant species. Transcriptional factors (TFs) are involved in plant defense regulations through acting as mediators by perceiving stress signals and directing downstream defense gene expression. The cross interactions of TFs and stress signaling crosstalk are decisive in determining accumulation of defense metabolites. Here, we collected the major TFs that are efficient in stress responses through regulating secondary metabolism for the direct cessation of stress factors. We focused on six major TF families including AP2/ERF, WRKY, bHLH, bZIP, MYB, and NAC. This review is the compilation of studies where researches were conducted to explore the roles of TFs in stress responses and the contribution of secondary metabolites in combating stress influences. Modulation of these TFs at transcriptional and post-transcriptional levels can facilitate molecular breeding and genetic improvement of crop plants regarding stress sensitivity and response through production of defensive compounds.
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Activity of MCPIP1 RNase in tumor associated processes.
Miekus, K, Kotlinowski, J, Lichawska-Cieslar, A, Rys, J, Jura, J
Journal of experimental & clinical cancer research : CR. 2019;(1):421
Abstract
The monocyte chemoattractant protein-induced protein (MCPIP) family consists of 4 members (MCPIP1-4) encoded by the ZC3h12A-D genes, which are located at different loci. The common features of MCPIP proteins are the zinc finger domain, consisting of three cysteines and one histidine (CCCH), and the N-terminal domain of the PilT protein (PilT-N-terminal domain (PIN domain)). All family members act as endonucleases controlling the half-life of mRNA and microRNA (miRNA). The best-studied member of this family is MCPIP1 (also known as Regnase-1).In this review, we discuss the current knowledge on the role of MCPIP1 in cancer-related processes. Because the characteristics of MCPIP1 as a fundamental negative regulator of immune processes have been comprehensively described in numerous studies, we focus on the function of MCPIP1 in modulating apoptosis, angiogenesis and metastasis.
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Simulation of the Dynamics of Primary Immunodeficiencies in B Cells.
Teku, GN, Vihinen, M
Frontiers in immunology. 2018;:1785
Abstract
Primary immunodeficiencies (PIDs) are a group of over 300 hereditary, heterogeneous, and mainly rare disorders that affect the immune system. Various aspects of immune system and PID proteins and genes have been investigated and facilitate systems biological studies of effects of PIDs on B cell physiology and response. We reconstructed a B cell network model based on data for the core B cell receptor activation and response processes and performed semi-quantitative dynamic simulations for normal and B cell PID failure modes. The results for several knockout simulations correspond to previously reported molecular studies and reveal novel mechanisms for PIDs. The simulations for CD21, CD40, LYN, MS4A1, ORAI1, PLCG2, PTPRC, and STIM1 indicated profound changes to major transcription factor signaling and to the network. Significant effects were observed also in the BCL10, BLNK, BTK, loss-of-function CARD11, IKKB, MALT1, and NEMO, simulations whereas only minor effects were detected for PIDs that are caused by constitutively active proteins (PI3K, gain-of-function CARD11, KRAS, and NFKBIA). This study revealed the underlying dynamics of PID diseases, confirms previous observations, and identifies novel candidates for PID diagnostics and therapy.
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Extracellular osmolarity regulates matrix homeostasis in the intervertebral disc and articular cartilage: evolving role of TonEBP.
Johnson, ZI, Shapiro, IM, Risbud, MV
Matrix biology : journal of the International Society for Matrix Biology. 2014;:10-6
Abstract
Degeneration of the intervertebral disc is characterized by changes in proteoglycan status, loss of bound water molecules, decreased tissue osmotic pressure and a resulting mechanical failure of the disc. A similar spectrum of changes is evident in osteoarthritic articular cartilage. When healthy, resident cells in these skeletal tissues respond to applied mechanical loads by regulating their own osmotic state and the hydration of the extracellular matrix. The transcription factor Tonicity-Responsive Enhancer Binding Protein (TonEBP or NFAT5) is known to mediate the osmoadaptive response in these and other tissues. While the molecular basis of how osmotic loading controls matrix homeostasis is not completely understood, TonEBP regulates the expression of aggrecan and β1,3-glucoronosyltransferase in nucleus pulposus cells, in addition to targets that allow for survival under hypertonic stress. Moreover, in chondrocytes, TonEBP controls expression of several collagen subtypes and Sox9, a master regulator of aggrecan and collagen II expression. Thus, TonEBP-mediated regulation of the matrix composition allows disc cells and chondrocytes to modify the extracellular osmotic state itself. On the other hand, TonEBP in immune cells induces expression of TNF-α, ΙL-6 and MCP-1, pro-inflammatory molecules closely linked to matrix catabolism and pathogenesis of both disc degeneration and osteoarthritis, warranting investigations of this aspect of TonEBP function in skeletal cells. In summary, the TonEBP system, through its effects on extracellular matrix and osmoregulatory genes can be viewed primarily as a protective or homeostatic response to physiological loading.
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Peroxide-sensing transcriptional regulators in bacteria.
Dubbs, JM, Mongkolsuk, S
Journal of bacteriology. 2012;(20):5495-503
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Abstract
The ability to maintain intracellular concentrations of toxic reactive oxygen species (ROS) within safe limits is essential for all aerobic life forms. In bacteria, as well as other organisms, ROS are produced during the normal course of aerobic metabolism, necessitating the constitutive expression of ROS scavenging systems. However, bacteria can also experience transient high-level exposure to ROS derived either from external sources, such as the host defense response, or as a secondary effect of other seemingly unrelated environmental stresses. Consequently, transcriptional regulators have evolved to sense the levels of ROS and coordinate the appropriate oxidative stress response. Three well-studied examples of these are the peroxide responsive regulators OxyR, PerR, and OhrR. OxyR and PerR are sensors of primarily H(2)O(2), while OhrR senses organic peroxide (ROOH) and sodium hypochlorite (NaOCl). OxyR and OhrR sense oxidants by means of the reversible oxidation of specific cysteine residues. In contrast, PerR senses H(2)O(2) via the Fe-catalyzed oxidation of histidine residues. These transcription regulators also influence complex biological phenomena, such as biofilm formation, the evasion of host immune responses, and antibiotic resistance via the direct regulation of specific proteins.
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The role of NDR1 in pathogen perception and plant defense signaling.
Knepper, C, Savory, EA, Day, B
Plant signaling & behavior. 2011;(8):1114-6
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Abstract
The biochemical and cellular function of NDR1 in plant immunity and defense signaling has long remained elusive. Herein, we describe a novel role for NDR1 in both pathogen perception and plant defense signaling, elucidated by exploring a broader, physiological role for NDR1 in general stress responses and cell wall adhesion. Based on our predictive homology modeling, coupled with a structure-function approach, we found that NDR1 shares a striking similarity to mammalian integrins, well-characterized for their role in mediating the interaction between the extracellular matrix and stress signaling. ndr1-1 mutant plants exhibit higher electrolyte leakage following pathogen infection, compared to wild type Col-0. In addition, we observed an altered plasmolysis phenotype, supporting a role for NDR1 in maintaining cell wall-plasma membrane adhesions through mediating fluid loss under stress.
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Common themes emerge in the transcriptional control of T helper and developmental cell fate decisions regulated by the T-box, GATA and ROR families.
Miller, SA, Weinmann, AS
Immunology. 2009;(3):306-15
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Abstract
Cellular differentiation requires the precise action of lineage-determining transcription factors. In the immune system, CD4(+) T helper cells differentiate into at least three distinct effector lineages, T helper type 1 (Th1), Th2 and Th17, with the fate of the cell at least in part determined by the transcription factors T-box expressed in T cells (T-bet), GATA-3 and retinoid-related orphan receptor gammat (RORgammat), respectively. Importantly, these transcription factors are members of larger families that are required for numerous developmental transitions from early embryogenesis into adulthood. Mutations in members of these transcription factor families are associated with a number of human genetic diseases due to a failure in completing lineage-specification events when the factor is dysregulated. Mechanistically, there are both common and distinct functional activities that are utilized by T-box, GATA and ROR family members to globally alter the cellular gene expression profiles at specific cell fate decision checkpoints. Therefore, understanding the molecular events that contribute to the ability of T-bet, GATA-3 and RORgammat to define T helper cell lineages can provide valuable information relevant to the establishment of other developmental systems and, conversely, information from diverse developmental systems may provide unexpected insights into the molecular mechanisms utilized in T helper cell differentiation.