1. Intracellular Action of a Secreted Peptide Required for Fungal Virulence.
- Author
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Homer CM, Summers DK, Goranov AI, Clarke SC, Wiesner DL, Diedrich JK, Moresco JJ, Toffaletti D, Upadhya R, Caradonna I, Petnic S, Pessino V, Cuomo CA, Lodge JK, Perfect J, Yates JR 3rd, Nielsen K, Craik CS, and Madhani HD
- Subjects
- Animals, Cell Wall physiology, Cryptococcosis metabolism, Cryptococcus neoformans genetics, Disease Models, Animal, Fungal Proteins genetics, Fungal Proteins metabolism, Intercellular Signaling Peptides and Proteins genetics, Macrophages metabolism, Melanins metabolism, Membrane Transport Proteins genetics, Meningitis microbiology, Mice, Mice, Inbred C57BL, Mutation, Peptide Hydrolases metabolism, Quorum Sensing, Rabbits, Transcription Factors genetics, Transcription Factors metabolism, Virulence Factors genetics, Cryptococcosis microbiology, Cryptococcus neoformans metabolism, Cryptococcus neoformans pathogenicity, Intercellular Signaling Peptides and Proteins metabolism, Membrane Transport Proteins metabolism, Virulence Factors metabolism
- Abstract
Quorum sensing (QS) is a bacterial communication mechanism in which secreted signaling molecules impact population function and gene expression. QS-like phenomena have been reported in eukaryotes with largely unknown contributing molecules, functions, and mechanisms. We identify Qsp1, a secreted peptide, as a central signaling molecule that regulates virulence in the fungal pathogen Cryptococcus neoformans. QSP1 is a direct target of three transcription factors required for virulence, and qsp1Δ mutants exhibit attenuated infection, slowed tissue accumulation, and greater control by primary macrophages. Qsp1 mediates autoregulatory signaling that modulates secreted protease activity and promotes cell wall function at high cell densities. Peptide production requires release from a secreted precursor, proQsp1, by a cell-associated protease, Pqp1. Qsp1 sensing requires an oligopeptide transporter, Opt1, and remarkably, cytoplasmic expression of mature Qsp1 complements multiple phenotypes of qsp1Δ. Thus, C. neoformans produces an autoregulatory peptide that matures extracellularly but functions intracellularly to regulate virulence., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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