Abstract
Interferon-β (IFN-β) is a pleiotropic cytokine secreted in response to various pathological conditions and is clinically used for therapy of multiple sclerosis. Its application for treatment of cancer, infections and pulmonary diseases is limited by incomplete understanding of regulatory mechanisms of its functioning. Recently, we reported that IFN-β activity is affected by interactions with S100A1, S100A4, S100A6, and S100P proteins, which are members of the S100 protein family of multifunctional Ca2+-binding proteins possessing cytokine-like activities (Int J Mol Sci. 2020;21(24):9473). Here we show that IFN-β interacts with one more representative of the S100 protein family, the S100B protein, involved in numerous oncological and neurological diseases. The use of chemical crosslinking, intrinsic fluorescence, and surface plasmon resonance spectroscopy revealed IFN-β binding to Ca2+-loaded dimeric and monomeric forms of the S100B protein. Calcium depletion blocks the S100B–IFN-β interaction. S100B monomerization increases its affinity to IFN-β by 2.7 orders of magnitude (equilibrium dissociation constant of the complex reaches 47 pM). Crystal violet assay demonstrated that combined application of IFN-β and S100B (5–25 nM) eliminates their inhibitory effects on MCF-7 cell viability. Bioinformatics analysis showed that the direct modulation of IFN-β activity by the S100B protein described here could be relevant to progression of multiple oncological and neurological diseases.
Highlights
Interferon-β (IFN-β) is a four-helical cytokine secreted in response to various pathogens [1–3]
We show that one more member of the S100 protein family, the S100B protein, binds to IFN-β with even higher affinity, exerting more pronounced effect on the activity of this cytokine
The in vitro study presented here shows that the S100 proteins, which bind IFN-β, are not restricted to S100A1/A4/A6/P [30,31], and include the S100B protein
Summary
Interferon-β (IFN-β) is a four-helical cytokine secreted in response to various pathogens [1–3] It possesses immunomodulatory, anti/pro-inflammatory, antiviral, anti/promicrobial, and antitumor activities [1,4–7]. Despite the abundance of information on the downstream signaling events and the factors affecting IFN-β expression [2,3,27], the information on the direct modulation of IFN-β activity by extracellular soluble factors remains scarce To our knowledge, such cases are limited to IFN-β interactions with some representatives of the S100 protein family of multifunctional Ca2+-binding proteins with cytokine-like activities [28,29], including S100P [30] and S100A1/A4/A6 proteins [31]. Localization of S100B in cytosol/nucleus and its secretion favors S100B interaction with a broad spectrum of targets, including over 50 proteins [34,38] Kinetics oofftthheeiinntteerraaccttiioonnbbeetwtweeeennIFIFNN-β-βanadndCCa2a+-2b+o-buonudnSd10S01B00aBt 2a5t 2°C5 ◦(1Cm(1MmCMaCCla2,CplH2, p7H.4),7m.4)o,nmitoorneidtobreydSbPyR SspPeRctsrpoescctorpoyscuospiynguIsFinNg-βIFaNs -aβn aasnaalnytaen(a1l0y–t8e0(1n0M–8) 0anndMS)1a0n0Bd aSs10a0lBigaans da. lGigraenydc.uGrvreeys acurerveexspaerreimexepntearli,mwehnitlael,bwlahciklecbulravceks caurrevtehseaorreettihceaol,rceatilccaull,actaeldcualcactoerddainccgotroditnhge thoettehrehoegteenroeoguenseloiguasnldigmanoddeml o[1d]e(ls[e1e] T(saebeleTa1bfloer1thfoerftithteinfigttpinargapmaertaemrse)t.ers)
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