The Calcium Binding Protein S100A11 and Its Roles in Diseases

Abstract

The calcium binding protein S100 family in humans contains 21 known members, with each possessing a molecular weight between 10 and 14 kDa. These proteins are characterized by a unique helix-loop-helix EF hand motif, and often form dimers and multimers. The S100 family mainly exists in vertebrates and exerts its biological functions both inside cells as a calcium sensor/binding protein, as well as outside cells. S100A11, a member of the S100 family, may mediate signal transduction in response to internal or external stimuli and it plays various roles in different diseases such as cancers, metabolic disease, neurological diseases, and vascular calcification. In addition, it can function as chemotactic agent in inflammatory disease. In this review, we first detail the discovery of S100 proteins and their structural features, and then specifically focus on the tissue and organ expression of S100A11. We also summarize its biological activities and roles in different disease and signaling pathways, providing an overview of S100A11 research thus far.

Keywords: S100 proteins; S100A11; diseases; protein interaction; signaling pathways.

FIGURE 1

EF-hand domains of S100 family proteins and evolutionary relationships of S100A11 in different species. (A) The amino acid sequences of S100 proteins are from human, which can be found at UniProt (www.uniprot.org/). EF-hand 1 represents the non-canonical EF-hand, EF-hand 2 represents the canonical EF-hand. (B) The cladogram of CDS sequences of S100A11 gene in typical species of different families. The CDS sequences data are from NCBI (www.ncbi.nlm.nih.gov/).

FIGURE 2

The diagram of spatial structure of S100A11 protein. (A) Top panel, the 3D structure of human S100A11 homodimer. Bottom panel, the surface charge profile of 3D structure of S100A11 homodimer shown in the same orientation as top panel, the surfaces with negative charge, positive charge and hydrophobic are colored in red, blue and white, respectively. The PDB file that used to make the 3D structure of human S100A11 was from RCSB PDB (www.rcsb.org/structure/2LUC), the 3D structures were made by PyMOL software. (B) The pig (Sus scrofa) S100A11 homodimer with the calcium ions. The calcium ions are shown as pink balls. The PDB file that used to make the 3D structure of porcine S100A11 was from RCSB PDB (www.rcsb.org/structure/1qls), the 3D structures were made by PyMOL software.

FIGURE 3

The tissues expression profile of the S100A11 gene. (A) The expression profile of the S100A11 gene in human tissues. S100A11 is highly expressed in human skin, spleen, and lung, and its expression is lower in liver, brain, and skeletal muscle. The expression data are from GeneCards (www.genecards.org/). (B) The expression profile of the S100A11 gene in mouse tissues. S100A11 is highly expressed in mouse sWAT, lung, and kidney, and it has a lower distribution in the small intestine, brain, and liver. The expression data are from NCBI (www.ncbi.nlm.nih.gov/). sWAT, subcutaneous white adipose tissue.

FIGURE 4

Signaling pathways for Ca²⁺ and TGF-β-induced S100A11-mediated cell growth inhibition. Elemental Ca²⁺, or PKCα induced by Ca²⁺/TGF-β can promote the phosphorylation of S100A11. Phosphorylated S100A11 then translocates to the nucleus through binding to NUCLEOLIN. In the nucleus, S100A11 competes with Sp1/3 for binding to NUCLEOLIN. This then releases free Sp1/3 to induce p21 expression. Moreover, S100A11 can bind to SMAD2/3 and SMAD4, that has been stimulated by TGF-β, to form a complex. Subsequently, this complex migrates to the nucleus to induce p21 expression. In either case, increasing levels of p21 results in cell growth inhibition. The circled “P” represents phosphorylation.

FIGURE 5

Signaling pathways for S100A11-mediated cell proliferation and growth. (1) The Wnt signaling pathway. S100A11 accelerates the entry of β-Catenin into the nucleus, thereby regulating the downstream Wnt target genes. (2) The TGF-β signaling pathway. Under the stimulation of TGF-β, S100A11 promotes the SMAD2/3 to form a complex with SMAD4, the complex then enters into the nucleus and controls the expression of target genes. (3) The PI3K/AKT signaling pathway. S100A11 is first secreted outside the cell and then binds to the RAGE receptor to induce the expression of EGF genes through the Akt signaling pathway. CREB, cAMP response element-binding protein; EGFs, epidermal growth factors. (4) The NF-κB signaling pathway. S100A11 promotes the phosphorylation of I-κB, which then leads to the activation and nuclear migration of NF-κB to regulate the expression of target genes. All of the above four processes ultimately promote cell proliferation and growth. The circled “P” represents phosphorylation.

FIGURE 6

The involvement of S100A11 in TNF-α, CXCLs, and IL-1β induced inflammation. TNF-α, CXCL8, and IL-1β induce the expression of S100A11. Subsequently, S100A11 is secreted through a Caspase-1 dependent manner. Extracellular S100A11 is dimerized under the catalysis of TG2, and then binds to the RAGE receptor to induce the expression of inflammatory genes through the p38 MAPK signaling pathway, which causes inflammation progression. CXCLs, CXC chemokine ligands; TG2, transglutaminase 2. The circled “P” represents phosphorylation.

FIGURE 7

S100A11-HDAC6-FOXO1 axis in the regulation of autophagy and lipogenesis in liver induced by high fat diet. Dietary lipids induce the overexpression of S100A11. S100A11 then competes with FOXO1 for binding to HDAC6, which releases and promotes the acetylation of FOXO1. The acetylated FOXO1 activates autophagy and lipogenesis pathways leading to lipid droplet accumulation. HDAC6, histone deacetylase 6; FOXO1, forkhead box protein O1. The circled “Ac” represents acetylation.