Galectin 3: an extraordinary multifunctional protein in dermatology. Current knowledge and perspectives

Galectin-3 (Gal-3) is an evolutionarily conserved and multifunctional protein that drives inflammation in disease. Gal-3′s role in the central nervous system has been less studied than in the immune system. However, recent studies show it exacerbates Alzheimer’s disease and is upregulated in a large variety of brain injuries, while loss of Gal-3 function can diminish symptoms of neurodegenerative diseases such as Alzheimer’s. Several novel molecular pathways for Gal-3 were recently uncovered. It is a natural ligand for TREM2 (triggering receptor expressed on myeloid cells), TLR4 (Toll-like receptor 4), and IR (insulin receptor). Gal-3 regulates a number of pathways including stimulation of bone morphogenetic protein (BMP) signaling and modulating Wnt signalling in a context-dependent manner. Gal-3 typically acts in pathology but is now known to affect subventricular zone (SVZ) neurogenesis and gliogenesis in the healthy brain. Despite its myriad interactors, Gal-3 has surprisingly specific and important functions in regulating SVZ neurogenesis in disease. Gal-1, a similar lectin often co-expressed with Gal-3, also has profound effects on brain pathology and adult neurogenesis. Remarkably, Gal-3′s carbohydrate recognition domain bears structural similarity to the SARS-CoV-2 virus spike protein necessary for cell entry. Gal-3 can be targeted pharmacologically and is a valid target for several diseases involving brain inflammation. The wealth of molecular pathways now known further suggest its modulation could be therapeutically useful.

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Versatility of USP18 in physiology and pathophysiology

Acta Biochimica Polonica ◽

10.18388/abp.2019_2844 ◽

2019 ◽

Author(s):

Paulina Dziamałek-Macioszczyk ◽

Joanna Haraźna ◽

Tomasz Stompór

Keyword(s):

Bacterial Infections ◽

Current Knowledge ◽

Cell Signalling ◽

Signalling Pathways ◽

Type I ◽

Multifunctional Protein ◽

Enzymatic Function ◽

Multiple Processes ◽

Specific Protease ◽

Interferon Stimulated Gene 15

Ubiquitin-specific peptidase 18 (USP18) is a multifunctional protein and its roles are still being investigated. This enzyme removes ubiquitin-like molecules from their substrates and the only known interferon-stimulated gene 15 (ISG15) specific protease. Apart from its enzymatic function, it also inhibits interferon type I and III signalling pathways. USP18 is known to regulate multiple processes, such as: cell cycle, cell signalling and response to viral and bacterial infections. Moreover, it contributes to the development of several autoimmune diseases and carcinogenesis, and recently was described as a cardiac remodelling inhibitor. This review summarizes the current knowledge on USP18 functions, highlighting its contribution to the development of heart failure, given the fact that this disease’s etiology is now considered to be inflammatory in nature.

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Unraveling the Role of ACE2, the Binding Receptor for SARS-CoV-2, in Inflammatory Bowel Disease

Inflammatory Bowel Diseases ◽

10.1093/ibd/izaa249 ◽

2020 ◽

Vol 26 (12) ◽

pp. 1787-1795 ◽

Cited By ~ 1

Author(s):

Mariana Ferreira-Duarte ◽

Maria Manuela Estevinho ◽

Margarida Duarte-Araújo ◽

Fernando Magro ◽

Manuela Morato

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Intestinal Inflammation ◽

Current Knowledge ◽

Renin Angiotensin System ◽

Biologic Drugs ◽

Multifunctional Protein ◽

Expression Activity ◽

Inflammatory Bowel ◽

The Impact

Abstract Angiotensin-converting enzyme 2 (ACE2) has been highlighted for its role as a receptor for SARS-CoV-2, responsible for the current COVID-19 pandemic. This review summarizes current knowledge about ACE2 as a multifunctional protein, focusing on its relevance in inflammatory bowel disease (IBD). As an enzyme, ACE2 may be protective in IBD because it favors the counter-regulatory arm of the renin-angiotensin system or deleterious because it metabolizes other anti-inflammatory/repairing elements. Meanwhile, as a receptor for SARS-CoV-2, the impact of ACE2 expression/activity on infection is still under debate because no direct evidence has been reported and, again, both protective and deleterious pathways are possible. Research has shown that ACE2 regulates the expression of the neutral amino acid transporter B0AT1, controlling tryptophan-associated intestinal inflammation and nutritional status. Finally, intact membrane-bound or shed soluble ACE2 can also trigger integrin signaling, modulating the response to anti-integrin biologic drugs used to treat IBD (such as vedolizumab) and fibrosis, a long-term complication of IBD. As such, future studies on ACE2 expression/activity in IBD can improve monitoring of the disease and explore an alternative pharmacological target.

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Galectin-3 in Inflammasome Activation and Primary Biliary Cholangitis Development

International Journal of Molecular Sciences ◽

10.3390/ijms21145097 ◽

2020 ◽

Vol 21 (14) ◽

pp. 5097

Author(s):

Aleksandar Arsenijevic ◽

Bojana Stojanovic ◽

Jelena Milovanovic ◽

Dragana Arsenijevic ◽

Nebojsa Arsenijevic ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Animal Studies ◽

Current Knowledge ◽

Specific Binding ◽

Primary Biliary Cholangitis ◽

Inflammasome Activation ◽

Multimeric Complex ◽

Galectin 3 ◽

Binding Lectin

Primary biliary cholangitis (PBC) is a chronic inflammatory autoimmune liver disease characterized by inflammation and damage of small bile ducts. The NLRP3 inflammasome is a multimeric complex of proteins that after activation with various stimuli initiates an inflammatory process. Increasing data obtained from animal studies implicate the role of NLRP3 inflammasome in the pathogenesis of various diseases. Galectin-3 is a β-galactoside-binding lectin that plays important roles in various biological processes including cell proliferation, differentiation, transformation and apoptosis, pre-mRNA splicing, inflammation, fibrosis and host defense. The multilineage immune response at various stages of PBC development includes the involvement of Gal-3 in the pathogenesis of this disease. The role of Galectin-3 in the specific binding to NLRP3, and inflammasome activation in models of primary biliary cholangitis has been recently described. This review provides a brief pathogenesis of PBC and discusses the current knowledge about the role of Gal-3 in NLRP3 activation and PBC development.

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Serum Levels of Galectin-3: Possible Association with Fibrosis, Aberrant Angiogenesis, and Immune Activation in Patients with Systemic Sclerosis

The Journal of Rheumatology ◽

10.3899/jrheum.110755 ◽

2012 ◽

Vol 39 (3) ◽

pp. 539-544 ◽

Cited By ~ 26

Author(s):

TAKASHI TANIGUCHI ◽

YOSHIHIDE ASANO ◽

KANAME AKAMATA ◽

SHINJI NODA ◽

YURI MASUI ◽

...

Keyword(s):

Systemic Sclerosis ◽

Immune Activation ◽

Developmental Process ◽

Systolic Pressure ◽

Serum Levels ◽

Digital Ulcers ◽

Healthy Controls ◽

Ventricular Systolic Pressure ◽

Multifunctional Protein ◽

Galectin 3

Objective.Galectin-3 is a multifunctional protein implicated in a variety of biological processes including fibrosis, angiogenesis, and immune activation, all of which are associated with the development of systemic sclerosis (SSc). We investigated the clinical significance of serum galectin-3 levels in SSc.Methods.Serum galectin-3 levels were determined by a specific ELISA in 58 patients with SSc and 19 healthy controls.Results.Serum galectin-3 levels were significantly lower in patients with diffuse cutaneous SSc (dcSSc) than in controls (3.29 ± 3.27 ng/ml vs 4.91 ± 2.67 ng/ml, respectively; p < 0.05), while being comparable between limited cutaneous SSc (3.70 ± 2.39 ng/ml) and healthy controls. In dcSSc, serum galectin-3 levels significantly correlated with total skin score (r = 0.45, p < 0.05). Serum galectin-3 levels were significantly decreased in early dcSSc (disease duration < 1 year; 1.64 ± 1.74 ng/ml; p < 0.05), but not in mid-stage dcSSc (1 to 6 years; 3.22 ± 3.16 ng/ml) or late-stage dcSSc (> 6 years; 4.86 ± 4.10 ng/ml), compared with controls. Serum galectin-3 levels were higher in SSc patients with both digital ulcers (DU) and elevated right ventricular systolic pressure (RVSP) than in those without each symptom (DU: 5.44 ± 3.74 ng/ml vs 2.99 ± 2.36 ng/ml, p < 0.05; elevated RVSP: 4.44 ± 3.14 ng/ml vs 2.82 ± 2.64 ng/ml, p < 0.05).Conclusion.Galectin-3 may be related to the developmental process of skin sclerosis in dcSSc and of DU and pulmonary vascular involvements in total SSc.

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Roles of CD38 in the Immune Response to Infection

Cells ◽

10.3390/cells9010228 ◽

2020 ◽

Vol 9 (1) ◽

pp. 228 ◽

Cited By ~ 8

Author(s):

Estibaliz Glaría ◽

Annabel F. Valledor

Keyword(s):

Immune Response ◽

Cell Activation ◽

Current Knowledge ◽

Biological Fluids ◽

Functional Expression ◽

Infectious Complications ◽

Soluble Form ◽

Multifunctional Protein ◽

Cd38 Expression ◽

Parasitic Pathogens

CD38 is a multifunctional protein widely expressed in cells from the immune system and as a soluble form in biological fluids. CD38 expression is up-regulated by an array of inflammatory mediators, and it is frequently used as a cell activation marker. Studies in animal models indicate that CD38 functional expression confers protection against infection by several bacterial and parasitic pathogens. In addition, infectious complications are associated with anti-CD38 immunotherapy. Although CD38 displays receptor and enzymatic activities that contribute to the establishment of an effective immune response, recent work raises the possibility that CD38 might also enhance the immunosuppressive potential of regulatory leukocytes. This review integrates the current knowledge on the diversity of functions mediated by CD38 in the host defense to infection.

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Multifunctional YY1 in Liver Diseases

Seminars in Liver Disease ◽

10.1055/s-0037-1607451 ◽

2017 ◽

Vol 37 (04) ◽

pp. 363-376 ◽

Cited By ~ 5

Author(s):

Shuang Yang ◽

Jian Zhou ◽

Weiwu Gao ◽

Xia Yang ◽

Di Yang ◽

...

Keyword(s):

Liver Diseases ◽

Drug Targets ◽

Current Knowledge ◽

Cell Types ◽

Bile Acid Metabolism ◽

Multifunctional Protein ◽

Yin Yang 1 ◽

B Virus ◽

Cellular Context ◽

Underlying Mechanisms

AbstractThe transcription factor Yin Yang 1 (YY1) is a multifunctional protein that can activate or repress gene expression, depending on the cellular context. While YY1 is ubiquitously expressed and highly conserved between species, its role varies among the diverse cell types and includes proliferation, differentiation, and apoptosis. Upregulated YY1 expression is found in pathogenic conditions, such as human hepatocellular carcinoma and hepatitis B virus infection, and its roles in the molecular pathogenic mechanisms in liver (i.e., fibrosis, carcinogenesis, viral-induced injury) are currently being elucidated. The most recent studies have revealed that YY1 is deeply involved in such dysregulated cellular metabolisms as glycometabolism, lipid metabolism, and bile acid metabolism, which are all involved in various diseases. In this review, we will summarize the current knowledge on YY1 in liver diseases, providing a focused discussion on the characterized and probable underlying mechanisms, as well as a reasoned evaluation of the potential for YY1-mediated pathology as drug targets in liver disease therapies.

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The Role of DJ-1 in Cellular Metabolism and Pathophysiological Implications for Parkinson’s Disease

Cells ◽

10.3390/cells10020347 ◽

2021 ◽

Vol 10 (2) ◽

pp. 347

Author(s):

Pauline Mencke ◽

Ibrahim Boussaad ◽

Chiara D. Romano ◽

Toshimori Kitami ◽

Carole L. Linster ◽

...

Keyword(s):

Parkinson’S Disease ◽

Chronic Diseases ◽

Metabolic Pathways ◽

Potential Role ◽

Current Knowledge ◽

Cellular Metabolism ◽

Metabolic Effects ◽

Physiological Functions ◽

Multifunctional Protein

DJ-1 is a multifunctional protein associated with pathomechanisms implicated in different chronic diseases including neurodegeneration, cancer and diabetes. Several of the physiological functions of DJ-1 are not yet fully understood; however, in the last years, there has been increasing evidence for a potential role of DJ-1 in the regulation of cellular metabolism. Here, we summarize the current knowledge on specific functions of DJ-1 relevant to cellular metabolism and their role in modulating metabolic pathways. Further, we illustrate pathophysiological implications of the metabolic effects of DJ-1 in the context of neurodegeneration in Parkinson´s disease.

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ZNF224 Protein: Multifaceted Functions Based on Its Molecular Partners

Molecules ◽

10.3390/molecules26206296 ◽

2021 ◽

Vol 26 (20) ◽

pp. 6296

Author(s):

Elena Cesaro ◽

Angelo Lupo ◽

Roberta Rapuano ◽

Arianna Pastore ◽

Michela Grosso ◽

...

Keyword(s):

Dna Binding ◽

Zinc Finger ◽

Protein Interactions ◽

Transcriptional Repression ◽

Zinc Finger Protein ◽

Current Knowledge ◽

Protein Protein Interactions ◽

Multifunctional Protein ◽

Finger Protein ◽

Zinc Finger Domains

The transcription factor ZNF224 is a Kruppel-like zinc finger protein that consists of 707 amino acids and contains 19 tandemly repeated C2H2 zinc finger domains that mediate DNA binding and protein–protein interactions. ZNF224 was originally identified as a transcriptional repressor of genes involved in energy metabolism, and it was demonstrated that ZNF224-mediated transcriptional repression needs the interaction of its KRAB repressor domain with the co-repressor KAP1 and its zinc finger domains 1–3 with the arginine methyltransferase PRMT5. Furthermore, the protein ZNF255 was identified as an alternative isoform of ZNF224 that possesses different domain compositions mediating distinctive functional interactions. Subsequent studies showed that ZNF224 is a multifunctional protein able to exert different transcriptional activities depending on the cell context and the variety of its molecular partners. Indeed, it has been shown that ZNF224 can act as a repressor, an activator and a cofactor for other DNA-binding transcription factors in different human cancers. Here, we provide a brief overview of the current knowledge on the multifaceted interactions of ZNF224 and the resulting different roles of this protein in various cellular contexts.

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Pituitary tumor-transforming gene and its binding factor in endocrine cancer

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399410001699 ◽

2010 ◽

Vol 12 ◽

Cited By ~ 31

Author(s):

Vicki E. Smith ◽

Jayne A. Franklyn ◽

Christopher J. McCabe

Keyword(s):

Pituitary Tumor ◽

Current Knowledge ◽

Cellular Transformation ◽

Ovarian Carcinomas ◽

Pituitary Tumor Transforming Gene ◽

Multifunctional Protein ◽

Binding Factor ◽

Transforming Gene

The pituitary tumor-transforming gene (PTTG1) encodes a multifunctional protein (PTTG) that is overexpressed in numerous tumours, including pituitary, thyroid, breast and ovarian carcinomas. PTTG induces cellular transformation in vitro and tumourigenesis in vivo, and several mechanisms by which PTTG contributes to tumourigenesis have been investigated. Also known as the human securin, PTTG is involved in cell cycle regulation, controlling the segregation of sister chromatids during mitosis. This review outlines current information regarding PTTG structure, expression, regulation and function in the pathogenesis of neoplasia. Recent progress concerning the use of PTTG as a prognostic marker or therapeutic target will be considered. In addition, the PTTG binding factor (PBF), identified through its interaction with PTTG, has also been established as a proto-oncogene that is upregulated in several cancers. Current knowledge regarding PBF is outlined and its role both independently and alongside PTTG in endocrine and related cancers is discussed.

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