The Candida albicans toxin candidalysin mediates distinct epithelial inflammatory responses through p38 and EGFR-ERK pathways

Abstract

The fungal pathogen Candida albicans secretes the peptide toxin candidalysin, which damages epithelial cells and drives an innate inflammatory response mediated by the epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MAPK) pathways and the transcription factor c-Fos. In cultured oral epithelial cells, candidalysin activated the MAPK p38, which resulted in heat shock protein 27 (Hsp27) activation, IL-6 release, and EGFR phosphorylation without affecting the induction of c-Fos. p38 activation was not triggered by EGFR but by two nonredundant pathways involving MAPK kinases (MKKs) and the kinase Src, which differentially controlled p38 signaling outputs. Whereas MKKs mainly promoted p38-dependent release of IL-6, Src promoted p38-mediated phosphorylation of EGFR in a ligand-independent fashion. In parallel, candidalysin also activated the EGFR-ERK pathway in a ligand-dependent manner, resulting in c-Fos activation and release of the neutrophil-activating chemokines G-CSF and GM-CSF. In mice, early clearance events of oral C. albicans infection required p38 but not c-Fos. These findings delineate how candidalysin activates the pathways downstream of the MAPKs p38 and ERK that differentially contribute to immune activation during C. albicans infection.

Receptor-kinase EGFR-MAPK adaptor proteins mediate the epithelial response to Candida albicans via the cytolytic peptide toxin, candidalysin

“…Our data show that ERK1/2 is the major pathway activated by the EGFR adaptors, rather than p38 or SAPK/JNK, which is in agreement with work showing that candidalysin activates p38 J o u r n a l P r e -p r o o f independently of EGFR and ERK1/2 and that the EGFR-ERK1/2-c-Fos pathway is downstream of p38 (11). During infection with C. albicans, MAPK signaling is regulated by MKP1/DUSP1, with ERK1/2 mediating a negative feedback loop to coordinate the innate immune response (25).…”

“…Clys is generated by processing of its parent protein Ece1p by the kexin proteases ( 6 , 7 ). Clys secretion triggers epithelial cell damage and activation of a mitogen-activated protein kinase (MAPK)–based signaling pathway that leads to secretion of inflammatory mediators and cell survival signals ( 8 , 9 , 10 , 11 ). The epidermal growth factor receptor (EGFR) is key for mediating the host immune response against several microbial pathogens ( 12 ), including C. albicans ( 13 , 14 , 15 , 16 , 17 ).…”

EGFR-MAPK adaptor proteins mediate the epithelial response to Candida albicans via the cytolytic peptide toxin, candidalysin

“…Our data show that ERK1/2 is the major pathway activated by the EGFR adaptors, rather than p38 or SAPK/JNK, which is in agreement with work showing that candidalysin activates p38 independently of EGFR and ERK1/2 and that the EGFR-ERK1/2-c-Fos pathway is downstream of p38 (11). During infection with C. albicans, MAPK signaling is regulated by MKP1/DUSP1, with ERK1/2 mediating a negative feedback loop to coordinate the innate immune response (25).…”

“…Candidalysin is generated by processing of its parent protein Ece1p by the kexin proteases (6,7). Candidalysin secretion triggers epithelial cell damage and activation of a mitogen-activated protein kinase (MAPK)-based signaling pathway that leads to secretion of inflammatory mediators and cell survival signals (8)(9)(10)(11). The epidermal growth factor receptor (EGFR) is key for mediating the host immune response against several microbial pathogens (12), including C. albicans (13)(14)(15)(16)(17).…”

Piezo1 activates non-canonical EGFR endocytosis and signaling

“…We also identify a new essential role for SFKs in ligand-independent EGFR signaling. This could expand previous findings that SFKs activate p38 in response to radiation and to Candida infections to promote survival and infection clearance (58, 59), respectively, via ligand independent EGFR signaling. Together, these observations propose p38 as a general transactivator of EGFR in response to stressors, with a pro-survival and regenerative signaling output different from ligand-induced canonical responses.…”