Lestaurtinib br Conclusions br Acknowledgements We would lik

Conclusions
Acknowledgements We would like to thank the members of the Bergmann lab for fruitful discussions in the course of this work. This work was supported by the National Institute of General Medical Sciences (NIGMS) under award number R35 GM118330. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Introduction Staphylococcus aureus is one of the most infamous human pathogens, causing diseases from mild skin and wound infections to fatal sepsis or multiple organ failure (Yang et al., 2017). During infection, S. aureus can induce cell apoptosis through various pathways (Grassḿ et al., 2001). Apoptosis is a programmed cell death procedure that relies on an active cascade of cysteine endopeptidases called caspases (Fink and Cookson, 2005). Accumulated research data showed that apoptosis is pivotal in certain diseases caused by S. aureus, such as atopic dermatitis (AD) and sepsis (Ayala et al., 2007, Xu and Mccormick, 2012, Aziz et al., 2014). Cell apoptosis of the host immune system may conceivably facilitate S. aureus infection, and apoptosis of tissue Lestaurtinib can also trim the immune response by influencing cytokine production and T cell differentiation (Torchinsky et al., 2010). Thus, apoptosis can significantly affect S. aureus pathogenesis. A remarkable feature of S. aureus is its vast arsenal of virulence factors, including toxins and other molecules that increase the potential of diseases. Toxins are secreted poisonous substances that directly interfere with the host; toxins have three categories, namely, membrane-damaging toxins, toxins that interfere with receptors, and secreted enzymes (Otto, 2014). Many S. aureus toxins, such as staphylococcal enterotoxins (SEs) and alpha-toxin (α-toxin), show proapoptotic activities (Ulett and Adderson, 2006). However, the exact apoptotic cell types induced by S. aureus toxins and the underlying mechanisms are still obscure. In this review, we focus on the apoptosis brought by S. aureus toxins and the mechanisms by which they induce apoptosis. However, other virulence factors, including surface-located proteins, such as staphylococcal protein A (SPA), also potentially trigger apoptosis (Das et al., 2002). In line with the abovementioned definition of toxins, these virulence factors will not be discussed in this review.
Membrane-damaging toxins Membrane-damaging toxins can be further divided into two, namely, those that lyse cells dependently on initial receptor interaction and those that interfere with membranes without receptor interaction (Otto, 2014). Although S. aureus possesses many membrane-damaging toxins, including hemolysins, bi-component leukocidins, and phenol-soluble modulins, only α-toxin (α-hemolysin) and Panton-Valentine leukocidin (PVL) were capable of promoting apoptosis. However, α-toxin and PVL have different apoptosis-inducing abilities.
Enterotoxin superfamily The only proapoptotic toxins in the second category belong to the enterotoxin superfamily, which consists of SEs, the staphylococcal enterotoxin-like (SELs) proteins, and toxic shock syndrome toxin-1 (TSST-1). SEs were originally named based on their abilities to cause food poisoning and included at least 10 members, namely SEA, SEB, SEC, SED, SEE, SEG, SEH, SEI, SER, and SET. SEs are sometimes referred to as staphylococcal super antigens (SAgs) because of their abilities to activate T cells and to stimulate hyper-inflammatory responses (TSST-1 was terminated SEF before and also acted as a superantigen). SEL proteins, including SELJ, SELK, SELL, SELM, SELN, SELO, SELP, SELQ, SELS, SELU, SELV, and SELX, are homologous and are structurally similar to the SEs. However, SEL proteins can neither induce emesis nor activate T cells unlike SEs (Xu and Mccormick, 2012). The common structure of this protein superfamily consists of an N-terminal β-barrel motif similar to an OB-fold, which can bind to the Vβ region of the T cell receptor (TCR), and a C-terminal β-grasp motif that can ligate with type II major histocompatibility complex (MHCII) molecules. Proteins from the enterotoxin superfamily can be classified into five groups based on their structure and homology. Group I only has TSST-1. Given its truncated C-terminal, TSST-1 ligates to MHCII at a low affinity and does not induce emesis. However, TSST-1 can still bind to TCR and triggers toxic shock syndrome. SEB and SEC belong to group II and have a low-affinity MHCII α-chain binding domain in the C-terminal. SEA, SED, SEE, and SEH fall under group III and contain a high-affinity and zinc-dependent MHC II β-chain binding domain in addition to the low-affinity α-chain binding domain, so group III toxins can crosslink MHC II molecules. Both Group II and III toxins contain a unique cysteine-loop structure that is important for emetic activity. All Group IV toxins are streptococcal SAgs and are therefore beyond the scope of this review. Group V toxins contain mostly staphylococcal SAgs that do not cause emesis (Pinchuk et al., 2010, Spaulding et al., 2013). SEs showed diverse apoptosis-activating abilities among family members. Even a given SE can yield a different apoptosis-inducing effect in different cell types.