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Irisin As a Multifunctional Protein: Implications for Health and Certain Diseases

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Irisin As a Multifunctional Protein: Implications for Health and Certain Diseases View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Jagiellonian Univeristy Repository medicina Review Irisin as a Multifunctional Protein: Implications for Health and Certain Diseases Paulina Korta 1 , Ewa Poche´c 1,* and Agnieszka Mazur-Biały 2 1 Department of Glycoconjugate Biochemistry, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Gronostajowa 9, 30-387 Krakow, Poland 2 Department of Ergonomics and Exercise Physiology, Faculty of Health Sciences, Jagiellonian University, Medical College, Grzegorzecka 20, 31-531 Krakow, Poland * Correspondence: [email protected]; Tel.: +48-12-664-64-67 Received: 29 June 2019; Accepted: 12 August 2019; Published: 15 August 2019 Abstract: Sedentary life style is considered to be an independent risk factor for many disorders, including development of type 2 diabetes, obesity, immune dysfunction, asthma, and neurological or coronary heart disease. Irisin is released from myocytes during physical activity, and acts as a link between muscles and other tissues and organs. This myokine is produced as a result of proteolytic cleavage of FNDC5 protein present in the membrane of myocytes. Secretion of irisin is regulated by N-linked oligosaccharides attached to the protein molecule. The two N-glycan molecules, which constitute a significant part of the irisin glycoprotein, regulate the browning of adipocytes, which is the most important function of irisin. A receptor specific for irisin has still not been discovered. In some tissues irisin probably acts via integrins, which are widely expressed transmembrane receptors. Many studies have confirmed the multifunctional role of irisin and the beneficial effects of this molecule on body homeostasis. Irisin reduces systemic inflammation, maintains the balance between resorption and bone formation, and modulates metabolic processes and the functioning of the nervous system. It suppresses the expression and release of pro-inflammatory cytokines in obese individuals and attenuates inflammation in adipose tissue. The impact of irisin on cancer cell proliferation, migration, and invasion has also been demonstrated in numerous studies, which proves its role in carcinogenesis. Owing to these pleiotropic and beneficial properties, irisin may be a potential option to prevent and treat civilization-related diseases which are, nowadays, considered to be the major health problems in Western societies. Keywords: irisin; FNDC5; N-glycosylation; physical activity; obesity; inflammation; cancers 1. Introduction Skeletal muscle is the largest organ in the human body [1]. During or immediately after physical exercise myocytes secrete molecules called myokines, mainly chemokines and cytokines. Myokines regulate a variety of metabolic processes in various tissues and organs, such as liver, bones, brain, or fat tissue through endocrine, paracrine, or autocrine signaling pathways. The major myokines include interleukin 6 (IL-6), monocyte chemotactic protein 1 (MCP1), insulin-like growth factor-1 (IGF-1), and myostatin [2,3]. In 2012, Boström et al. reported the discovery of a new molecule that is secreted by myocytes. That molecule was able to induce changes in adipose tissue and activate thermogenesis [4]. Moreover, that molecule was proposed to act as a link between the muscles and other tissues of the body; the newly discovered protein has been called “irisin,” derived from the name of the Greek goddess Iris [5]. Since then, irisin has been the subject of extensive research, which enabled the gaining of insight into its pleiotropic properties. Medicina 2019, 55, 485; doi:10.3390/medicina55080485 www.mdpi.com/journal/medicina Medicina 2019,, 55,, 485x FOR PEER REVIEW 22 of of 14 2. Structure and N-Glycosylation of Irisin 2. Structure and N-Glycosylation of Irisin Irisin is a fragment of a cell membrane protein called fibronectin type III domain-containing proteinIrisin 5 (FNDC5/FRCP2/PeP) is a fragment of a cell [4]. membrane The FNDC5 protein protein called is composed fibronectin of 209 type amino III domain-containing acid (aa) residues. proteinIt contains 5 (FNDC5 an N-terminal/FRCP2 /signalPeP) [ 4sequence]. The FNDC5 built of protein 29 aa, is a composedfibronectin of type 209 III amino domain acid with (aa) 94 residues. aa, an Itunidentified contains an region N-terminal consisting signal of sequence 28 aa, a builttransmembrane of 29 aa, a fibronectin domain having type III 19 domain aa, and with a C- 94terminal aa, an unidentifiedpart with 39 aa region (Figure consisting 1). The C of-terminal 28 aa, a fragment transmembrane of FNDC5 domain is located having in the 19 aa,cytoplasm, and a C-terminal while the partextracellular with 39 aaN (Figure-terminal1). Thepotion C-terminal is proteolytically fragment ofcleaved FNDC5 to is produce located inirisin the cytoplasm,which is ultimately while the extracellularreleased into N-terminal the circulation potion [6,7 is]. proteolytically Both biochemical cleaved and to X produce-ray crystallography irisin which isstudies ultimately showed released that intoirisin the occurs circulation in the [form6,7]. Bothof homodimers, biochemical where and X-ray a β-sheet crystallography is created between studies showed the units. that This irisin structure occurs β inis stabilized the form of not homodimers, only by hydrogen where bonds, a -sheet but is also created by interactions between the between units. Thisthe side structure chains is of stabilized adjacent notsubunits, only byin hydrogenparticular bonds,, between but alsoArg- by75 interactionsand Glu-79, betweenwhich in the turn side protect chains the of adjacent dimer ends subunits, and inTrp particular,-90/Trp-90 between [8]. It was Arg-75 previously and Glu-79, esta whichblished in that turn protectirisin is the composed dimer ends of and112 Trp-90aa. The/Trp-90 mass [8of]. ItFNDC5 was previously proteins establishedrange from that 20 irisin to is32 composed kDa depending of 112 aa. on The the mass number of FNDC5 and proteins structure range of fromoligosaccharides 20 to 32 kDa (glycans) depending attached on the to number the protein and structure molecule of during oligosaccharides the post-translational (glycans) attached process toof theN-glycosylation protein molecule [4,9]. during the post-translational process of N-glycosylation [4,9]. Figure 1. FNDC5 structure and formation of irisin. The potential N--glycosylationglycosylation sites are marked as black dots.dots. Asn, Asn, asparagine; asparagine; GlcNAc, GlcNAc, N-acetylglucosamine; N-acetylglucosamine; Man, mannose;Man, mannose; Ser, serine; Ser, Thr, serine; threonine; Thr, X,threonine; any amino X, any acid amino except acid proline. except proline. Glycosylation i iss one of thethe mostmost commoncommon post-translationalpost-translational modificationsmodifications of proteins which occurs inin thethe lumen lumen of of endoplasmic endoplasmic reticulum reticulum and and the Golgithe Golgi apparatus. apparatus. More thanMore half than of allhalf proteins of all areproteins glycosylated, are glycosylated, mainly cell membranemainly cell and membrane secreted proteins. and secreted The attachment proteins. of carbohydrates,The attachment which of iscarbohydrates, a multi-stage processwhich is regulated a multi- bystage hundreds process of regulated enzymes, by leads hundreds to a great of heterogeneityenzymes, leads in theto a glycan great structures.heterogeneity Oligosaccharides in the glycan astructures.ffect the physicochemical Oligosaccharides properties affect the of proteins,physicochemical are necessary properties to obtain of theproteins, accurate are conformationnecessary to obtain of proteins, the accurate provide conformation protection against of proteins, proteolysis, provide and protection are important against for theirproteolysis, biological and functions are important in different for metabolictheir biological processes functions [10]. FNDC5 in different is an N metabolic-glycosylated processes protein [10]. and containsFNDC5 is oligosaccharides an N-glycosylated attached protein to the and asparagine contains residueoligosaccharides in the Asn–X–Ser attached/Thr to sequence the asparagine (where Xresidue is any aminoin the acidAsn except–X–Ser/Thr proline), sequence via a N (where-acetylglucosamine X is any amino residue acid (GlcNAc) except [11proline)]. Three, via main a groupsN-acetylglucosamine of N-glycan structures residue (GlcNAc) are linked [11]. via N Three-glycosidic main groups bonds toof Asn:N-glycan High-mannose structures/ oligomannoseare linked via type,N-glycosidic complex bonds type andto Asn: hybrid High type.-mannose/oligomannose All N-glycans contain type, the same complex pentasaccharide type and hybrid core buttype. di ffAerll inN- theglycans composition contain the of the same side pentasaccharide chains. The external core but portions differ of in high-mannose the composition glycans of the consist side chains. of 5–9 mannoseThe external (Man) portion residues.s Complex-typeof high-mannose oligosaccharides glycans consist are characterized of 5–9 mannose by a more diverse(Man) structuresresidues. composedComplex-type of GlcNAc, oligosaccharides galactose are (Gal), characterized fucose (Fuc), by a and more sialic diverse acid stru (SA)cture residues.s composed The hybrid-type of GlcNAc, galactose (Gal), fucose (Fuc), and sialic acid (SA) residues. The hybrid-type constitutes an Medicina 2019, 55, 485 3 of 14 Medicina 2019, 55, x FOR PEER REVIEW 3 of 14 intermediateconstitutes an class intermediate
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