Interferon-β Activity Is Affected by S100B Protein

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.

Calcium-Bound S100P Protein Is a Promiscuous Binding Partner of the Four-Helical Cytokines

“…The dissociation phases of the sensograms are biphasic revealing the existence of a relatively fast process and a much slower process. Both the processes are adequately described within the heterogeneous ligand model (1) ( Figure 1 , Figure 2 and Figure 3 , Table 3 ), which was previously successfully used for description of the S100-cytokine interactions [ 10 , 19 , 20 , 21 , 22 , 28 , 29 ]. The SPR data for IL-13 are described by the one-site binding scheme.…”

“…S100P binding could modify signaling of the S100P-specific cytokines, as exemplified by inhibition of the IFN-β-induced suppression of the viability of MCF-7 breast cancer cells by S100A1/A4/B/P proteins [ 10 , 19 , 20 ]. Another opportunity is the facilitation of secretion of the S100P-specific cytokines due to the S100P binding, as previously shown for the four-helical cytokine CLCF1, which needs association with the CRLF1 for efficient secretion [ 39 ].…”

“…Upon their release into extracellular space, some S100 proteins act similarly to cytokines in an autocrine/paracrine manner via recognition of cell surface receptors, including RAGE, TLR4, ErbB1, ErbB3, ErbB4, CD36, CD68, CD147, CD166, neuroplastin-β, 5-HT 1B , IL-10R, and SIRL-1 [ 2 , 10 , 18 ]. Furthermore, some of the extracellular S100 proteins are able to influence cytokine signaling via their direct binding; e.g., S100A1/A4/A6/B/P bind to IFN-β [ 10 , 19 , 20 ], distinct subsets of S100A1/A6/B/P interact with IL-6 family cytokines IL-11, OSM, CNTF, CT-1, and CLCF1 [ 21 ], S100A2/A6/P bind EPO [ 22 ], S100A4 binds to ErbB1 ligands [ 23 ], S100A13 interacts with IL1α/FGF1 [ 24 , 25 ], and S100B binds FGF2 [ 26 ]. Some of the S100-cytokine interactions could favor non-canonical secretion of both the interaction partners, as was shown for S100A13–IL1α/FGF1 [ 24 , 25 ].…”

Calcium-Bound S100P Protein is a Promiscuous Binding Partner of the Four-Helical Cytokines

“…The dissociation phases of the sensograms are biphasic revealing the existence of a relatively fast process and a much slower process. The both processes are adequately described within the heterogeneous ligand model (1) (Figures 1-3, Table 3), which was previously successfully used for description of the S100-cytokine interactions [10,[19][20][21][22]28,29]. The SPR data for IL-13 are described by the one-site binding scheme.…”

“…Upon release into extracellular space, some S100 proteins act similarly to cytokines in an autocrine/paracrine manner via recognition of cell surface receptors, including RAGE, TLR4, ErbB1, ErbB3, ErbB4, CD36, CD68, CD147, CD166, neuroplastin-β, 5-HT1B, IL-10R and SIRL-1 [2,10,18]. Furthermore, some of the extracellular S100 proteins are able to influence cytokine signaling via their direct binding; e.g., S100A1/A4/A6/B/P bind to IFN-β [10,19,20], distinct subsets of S100A1/A6/B/P interact with IL-6 family cytokines IL-11, OSM, CNTF, CT-1, and CLCF1 [21], S100A2/A6/P bind EPO [22], S100A4 binds to ErbB1 ligands [23], S100A13 interacts with IL1α/FGF1 [24,25], S100B binds FGF2 [26]. Some of the S100-cytokine interactions could favor non-canonical secretion of the both interaction partners, as was shown for S100A13 -IL1α/FGF1 [24,25].…”