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1.
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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2.
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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3.
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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4.
TRIM25 and its emerging RNA-binding roles in antiviral defense.
Choudhury, NR, Heikel, G, Michlewski, G
Wiley interdisciplinary reviews. RNA. 2020;(4):e1588
Abstract
The innate immune system is the body's first line of defense against viruses, with pattern recognition receptors (PRRs) recognizing molecules unique to viruses and triggering the expression of interferons and other anti-viral cytokines, leading to the formation of an anti-viral state. The tripartite motif containing 25 (TRIM25) is an E3 ubiquitin ligase thought to be a key component in the activation of signaling by the PRR retinoic acid-inducible gene I protein (RIG-I). TRIM25 has recently been identified as an RNA-binding protein, raising the question of whether its RNA-binding activity is important for its role in innate immunity. Here, we review TRIM25's mechanisms and pathways in noninfected and infected cells. We also introduce models that explain how TRIM25 binding to RNA could modulate its functions and play part in the antiviral response. These findings have opened new lines of investigations into functional and molecular roles of TRIM25 and other E3 ubiquitin ligases in cell biology and control of pathogenic infections. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA Interactions with Proteins and Other Molecules > Protein-RNA Recognition.
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5.
Transcription factors in ferroptotic cell death.
Dai, C, Chen, X, Li, J, Comish, P, Kang, R, Tang, D
Cancer gene therapy. 2020;(9):645-656
Abstract
Ferroptosis, a form of regulated cell death, is characterized by an excessive degree of iron accumulation and lipid peroxidation. Although it was originally identified only in cells expressing a mutant RAS oncogene, ferroptosis has also been found in normal cells following treatment by small molecules (e.g., erastin and RSL3) or drugs (e.g., sulfasalazine, sorafenib, and artesunate), which target antioxidant enzyme systems, especially the amino acid antiporter system xc- and the glutathione peroxidase GPX4. Dysfunctional ferroptosis is implicated in various physiological and pathological processes (e.g., metabolism, differentiation, and immunity). Targeting the ferroptotic network appears to a new treatment option for diseases or pathological conditions (e.g., cancer, neurodegeneration, and ischemia reperfusion injury). While the molecular machinery of ferroptosis remains largely unknown, several transcription factors (e.g., TP53, NFE2L2/NRF2, ATF3, ATF4, YAP1, TAZ, TFAP2C, SP1, HIF1A, EPAS1/HIF2A, BACH1, TFEB, JUN, HIC1, and HNF4A) play multiple roles in shaping ferroptosis sensitivity through either transcription-dependent or transcription-independent mechanisms. In this review, we summarize recent progress in understanding the transcriptional regulation underlying ferroptotic cell death, and discuss how it has provided new insights into cancer therapy.
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6.
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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7.
Zinc finger protein transcription factors: Integrated line of action for plant antimicrobial activity.
Noman, A, Aqeel, M, Khalid, N, Islam, W, Sanaullah, T, Anwar, M, Khan, S, Ye, W, Lou, Y
Microbial pathogenesis. 2019;:141-149
Abstract
The plants resist/tolerate unfavorable conditions in their natural habitats by using different but aligned and integrated defense mechanisms. Such defense responses include not only morphological and physiological adaptations but also the genomic and transcriptomic reconfiguration. Microbial attack on plants activates multiple pro-survival pathways such as transcriptional reprogramming, hypersensitive response (HR), antioxidant defense system and metabolic remodeling. Up-regulation of these processes during biotic stress conditions directly relates with plant survival. Over the years, hundreds of plant transcription factors (TFs) belonging to diverse families have been identified. Zinc finger protein (ZFP) TFs have crucial role in phytohormone response, plant growth and development, stress tolerance, transcriptional regulation, RNA binding and protein-protein interactions. Recent research progress has revealed regulatory and biological functions of ZFPs in incrementing plant resistance to pathogens. Integration of transcriptional activity with metabolic modulations has miniaturized plant innate immunity. However, the precise roles of different zinc finger TFs in plant immunity to pathogens have not been thoroughly analyzed. This review consolidates the pivotal functioning of zinc finger TFs and proposes the integrative understanding as foundation for the plant growth and development including the stress responses.
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8.
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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9.
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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10.
Functional studies of transcription factors involved in plant defenses in the genomics era.
Seo, E, Choi, D, Choi,
Briefings in functional genomics. 2015;(4):260-7
Abstract
Plant transcription factors (TFs) play roles in diverse biological processes including defense responses to pathogens. Here, we provide an overview of recent studies of plant TFs with regard to defense responses. TFs play roles in plant innate immunity by regulating genes related to pathogen-associated molecular pattern-triggered immunity, effector-triggered immunity, hormone signaling pathways and phytoalexin synthesis. Currently, genome-wide phylogenetic and transcriptomic analyses are as important as functional analyses in the study of plant TFs. The integration of genomics information with the knowledge obtained from functional studies provides new insights into the regulation of plant defense mechanisms as well as engineering crops with improved resistance to invading pathogens.