Abstract
c-Jun is a member of the early mammalian transcriptional regulators belonging to the AP-1 family, which participates in a wide range of cellular processes such as proliferation, apoptosis, tumorigenesis, and differentiation. Despite its established role in cell survival upon stress, its participation in the stress response induced by bacterial infections has been poorly investigated. To study the potential role of c-Jun in this context we choose the widely studied α-toxin produced by Staphylococcus aureus, a pore-forming toxin that is a critical virulence factor in the pathogenesis of these bacteria. We analyzed the effect of α-toxin treatment in the activation, expression, and protein levels of c-Jun in A549 lung epithelial cells. Furthermore, we explored the role of c-Jun in the cellular fate after exposure to α-toxin. Our results show that staphylococcal α-toxin per se is able to activate c-Jun by inducing phosphorylation of its Serine 73 residue. Silencing of the JNK (c-Jun N-terminal Kinase) signaling pathway abrogated most of this activation. On the contrary, silencing of the ERK (Extracellular Signal-Regulated Kinase) pathway exacerbated this response. Intriguingly, while the exposure to α-toxin induced a marked increase in the levels of c-Jun transcripts, c-Jun protein levels noticeably decreased in the same time-frame as a consequence of active proteolytic degradation through the proteasome-dependent pathway. In addition, we established that c-Jun promoted cell survival when cells were challenged with α-toxin. Similarly, c-Jun phosphorylation was also induced in cells upon intoxication with the cytolysin produced by Vibrio cholerae in a JNK-dependent manner, suggesting that c-Jun-JNK axis would be a conserved responsive cellular pathway to pore-forming toxins. This study contributes to understanding the role of the multifaceted c-Jun proto-oncoprotein in cell response to bacterial pore-forming toxins, positioning it as a relevant component of the complex early machinery mounted to deal with staphylococcal infections.
Highlights
Staphylococcus aureus is a primary health concern worldwide, being the etiological agent of diverse infections that span from mild to life-threatening (Chambers and Deleo, 2009; DeLeo et al, 2010)
In the present study we evaluated the effect of α-toxin, a main S. aureus virulence factor on c-Jun, a central early responsive cell cycle modulator that belongs to the AP-1 family of transcriptional regulators. c-Jun participates in a wide range of cellular functions such as proliferation, apoptosis, tumorigenesis and differentiation (Wisdom et al, 1999; Hess et al, 2004; Papoudou-Bai et al, 2016)
In this work we expand this range by providing insights in a poorly explored field of c-Jun, which is its role in the context of bacterial infections
Summary
Staphylococcus aureus is a primary health concern worldwide, being the etiological agent of diverse infections that span from mild to life-threatening (Chambers and Deleo, 2009; DeLeo et al, 2010). Monomers of Hla assemble to form a homoheptameric ring which pokes into the plasma membrane to function as a poreforming toxin (PFT) (Gouaux, 1998; Menestrina et al, 2001; Montoya and Gouaux, 2003), an intercommunicating 2 nm channel that leads to the loss of cellular potassium and calcium homeostasis (Below et al, 2009; Eichstaedt et al, 2009; Kloft et al, 2009; Eiffler et al, 2016) In this sense, it has been observed that staphylococcal α-toxin per se is able to trigger cellular defense responses such as production of IL-6 and IL-8, autophagy, and activation of p38 and ERK signaling pathways, among many others (Ratner et al, 2006; Gonzalez et al, 2008; Below et al, 2009; Kloft et al, 2009; Mestre et al, 2010). We expand the repertory of manifold functions known for c-Jun by enlisting it as part of the early cellular response to staphylococcal infections
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