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Interferon Beta Activity Is Modulated via Binding of Specific S100 Proteins.

ABSTRACT: Interferon-? (IFN-?) is a pleiotropic cytokine used for therapy of multiple sclerosis, which is also effective in suppression of viral and bacterial infections and cancer. Recently, we reported a highly specific interaction between IFN-? and S100P lowering IFN-? cytotoxicity to cancer cells (Int J Biol Macromol. 2020; 143: 633-639). S100P is a member of large family of multifunctional Ca²⁺-binding proteins with cytokine-like activities. To probe selectivity of IFN-?-S100 interaction with respect to S100 proteins, we used surface plasmon resonance spectroscopy, chemical crosslinking, and crystal violet assay. Among the thirteen S100 proteins studied S100A1, S100A4, and S100A6 proteins exhibit strictly Ca²⁺-dependent binding to IFN-? with equilibrium dissociation constants, K_d, of 0.04-1.5 µM for their Ca²⁺-bound homodimeric forms. Calcium depletion abolishes the S100-IFN-? interactions. Monomerization of S100A1/A4/A6 decreases K_d values down to 0.11-1.0 nM. Interferon-? is unable of binding to the S100 proteins studied. S100A1/A4 proteins inhibit IFN-?-induced suppression of MCF-7 cells viability. The revealed direct influence of specific S100 proteins on IFN-? activity uncovers a novel regulatory role of particular S100 proteins, and opens up novel approaches to enhancement of therapeutic efficacy of IFN-?.

SUBMITTER: Kazakov AS

PROVIDER: S-EPMC7764042 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Interferon Beta Activity Is Modulated via Binding of Specific S100 Proteins.

Kazakov Alexey S AS Sofin Alexander D AD Avkhacheva Nadezhda V NV Denesyuk Alexander I AI Deryusheva Evgenia I EI Rastrygina Victoria A VA Sokolov Andrey S AS Permyakova Maria E ME Litus Ekaterina A EA Uversky Vladimir N VN Permyakov Eugene A EA Permyakov Sergei E SE

International journal of molecular sciences 20201213 24

Interferon-β (IFN-β) is a pleiotropic cytokine used for therapy of multiple sclerosis, which is also effective in suppression of viral and bacterial infections and cancer. Recently, we reported a highly specific interaction between IFN-β and S100P lowering IFN-β cytotoxicity to cancer cells (Int J Biol Macromol. 2020; 143: 633-639). S100P is a member of large family of multifunctional Ca<sup>2+</sup>-binding proteins with cytokine-like activities. To probe selectivity of IFN-β-S100 interaction w ...[more]

PMID: 33322098

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Project description:BackgroundAmong the EF-Hand calcium-binding proteins the subgroup of S100 proteins constitute a large family with numerous and diverse functions in calcium-mediated signaling. The evolutionary origin of this family is still uncertain and most studies have examined mammalian family members.ResultsWe have performed an extensive search in several teleost genomes to establish the s100 gene family in fish. We report that the teleost S100 repertoire comprises fourteen different subfamilies which show remarkable similarity across six divergent teleost species. Individual species feature distinctive subsets of thirteen to fourteen genes that result from local gene duplications and gene losses. Eight of the fourteen S100 subfamilies are unique for teleosts, while six are shared with mammalian species and three of those even with cartilaginous fish. Several S100 family members are found in jawless fish already, but none of them are clear orthologs of cartilaginous or bony fish s100 genes. All teleost s100 genes show the expected structural features and are subject to strong negative selection. Many aspects of the genomic arrangement and location of mammalian s100 genes are retained in the teleost s100 gene family, including a completely conserved intron/exon border between the two EF hands. Zebrafish s100 genes exhibit highly specific and characteristic expression patterns, showing both redundancy and divergence in their cellular expression. In larval tissue expression is often restricted to specific cell types like keratinocytes, hair cells, ionocytes and olfactory receptor neurons as demonstrated by in situ hybridization.ConclusionThe origin of the S100 family predates at least the segregation of jawed from jawless fish and some extant family members predate the divergence of bony from cartilaginous fish. Despite a complex pattern of gene gains and losses the total repertoire size is remarkably constant between species. On the expression level the teleost S100 proteins can serve as precise markers for several different cell types. At least some of their functions may be related to those of their counterparts in mammals. Accordingly, our findings provide an excellent basis for future studies of the functions and interaction partners of s100 genes and finally their role in diseases, using the zebrafish as a model organism.

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Interferon Beta Activity Is Modulated via Binding of Specific S100 Proteins.

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Interferon Beta Activity Is Modulated via Binding of Specific S100 Proteins.

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