Nutritional Immunity: S100 Proteins at the Host-Pathogen Interface

Abstract

The S100 family of EF-hand calcium (Ca 2؉ )-binding proteins is essential for a wide range of cellular functions. During infection, certain S100 proteins act as damage-associated molecular patterns (DAMPs) and interact with pattern recognition receptors to modulate inflammatory responses. In addition, these inflammatory S100 proteins have potent antimicrobial properties and are essential components of the immune response to invading pathogens. In this review, we focus on S100 proteins that exhibit antimicrobial properties through the process of metal limitation, termed nutritional immunity, and discuss several recent advances in our understanding of S100 protein-mediated metal sequestration at the site of infection. S100 proteins are EF-hand Ca 2ϩ -binding proteins involved in a diverse array of both intracellular and extracellular regulatory functions (1-6). Over 20 S100 proteins have been identified, and all have a characteristic dimeric structure distinct from other EF-hand proteins (7). Like many EF-hand proteins, Ca 2ϩ signaling function is associated with a binding-induced conformational change exposing a hydrophobic patch that generates specificity for target proteins (8,9). Within the cell, S100 proteins regulate numerous important processes including Ca 2ϩ homeostasis, energy metabolism, and cell proliferation and differentiation. Remarkably, certain S100 proteins can be secreted and/or released by cells, and among these, some play an important role during infection and inflammation (1). In particular, extracellular S100 proteins can act as damage-associated molecular pattern (DAMP) 3 proteins and initiate a proinflammatory immune response through interaction with pattern recognition receptors and the receptor for advanced glycation end products (RAGE) (10, 11). Furthermore, through the process of nutrient metal limitation, several S100 proteins have been shown to be antimicrobial and play a key role in host defense at the host-pathogen interface (12)(13)(14)(15)(16)(17). In this review, we provide insight into structure and function of the three S100 proteins with antimicrobial and inflammatory properties: S100A7 (psoriasin); S100A8/S100A9 (calprotectin; calgranulin A and B; MRP-8 and 9); and S100A12 (calgranulin C). Key Properties of S100 Proteins with Antimicrobial Activity Structure and Metal BindingThe basic unit of EF-hand proteins is a helix-Ca 2ϩ binding loop-helix motif; these motifs are typically packed in pairs to form a stable globular four-helix bundle domain (8). Each S100 protein contains a distinctive S100-specific N-terminal EFhand motif and a C-terminal canonical EF-hand motif (Fig. 1). The fundamental structural unit of S100 proteins is a highly integrated antiparallel dimer (7); all S100 proteins form this structure as homodimers, and some will also heterodimerize. S100A8 and S100A9 are unique among all members of the family because they preferentially form a heterodimer (18), which is termed calprotectin based on its role in innate immunity. S100 proteins are also known to form high...

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