Bacterial peptidoglycan triggers Candida albicans hyphal growth by directly activating the adenylyl cyclase Cyr1p.
Human serum potently induces hyphal development of the polymorphic fungal pathogen Candida albicans, a phenotype that contributes critically to infections. The fungal adenylyl cyclase Cyr1p is a key component of the cAMP/PKA-signaling pathway that controls diverse infection-related traits, including hyphal morphogenesis. However, identity of the serum hyphal inducer(s) and its fungal sensor remain unknown. Our initial analyses of active serum fractions revealed signs of bacterial peptidoglycan (PGN)-like molecules. Here, we show that several purified and synthetic muramyl dipeptides (MDPs), subunits of PGN, can strongly promote C. albicans hyphal growth. Analogous to PGN recognition by the mammalian sensors Nod1 and Nod2 through their leucine-rich-repeat (LRR) domain, we show that MDPs activate Cyr1p by directly binding to its LRR domain. Given the abundance of PGN in the intestine, a natural habitat and invasion site for C. albicans, our findings have important implications for the mechanisms of infection by this pathogen.
Xu
Xiao-Li
XL
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A( *)STAR), 61 Biopolis Drive, Proteos, Singapore 138673.
Lee
Raymond Teck Ho
RT
Fang
Hao-Ming
HM
Wang
Yan-Ming
YM
Li
Rong
R
Zou
Hao
H
Zhu
Yong
Y
Wang
Yue
Y
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000302:isolation & purification / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D001419:Bacteria / Q000737:chemistry*; D015153:Blotting, Western; D002176:Candida albicans / Q000187:drug effects* / Q000254:growth & development*; D002851:Chromatography, High Pressure Liquid; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D025301:Hyphae / Q000254:growth & development*; D010457:Peptidoglycan / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D044967:Serum / Q000737:chemistry / Q000378:metabolism
D005656:Fungal Proteins; D010457:Peptidoglycan; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D000262:Adenylyl Cyclases