Intracellular Action of a Secreted Peptide Required for Fungal Virulence

Christina M. Homer, Diana K. Summers, Alexi I. Goranov, Starlynn C. Clarke, Darin L. Wiesner, Jolene K. Diedrich, James J. Moresco, Dena Toffaletti, Rajendra Upadhya, Ippolito Caradonna, Sarah Petnic, Veronica Pessino, Christina A. Cuomo, Jennifer K. Lodge, John Perfect, John R. Yates, Kirsten Nielsen, Charles S. Craik, Hiten D. Madhani

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)849-864
Number of pages16
JournalCell Host and Microbe
Volume19
Issue number6
DOIs
StatePublished - Jun 8 2016

Bibliographical note

Funding Information:
We thank members of the lab for helpful discussions, N. Nguyen for media preparation, members of the J. Cox lab for kind gifts of BMDMs and reagents, and J. Heitman for strains. Supported by R01AI096869, F30HL120496-01A1, P41RR011823, P41GM103533, R01AG027463, P50GM082250, AI080275, and R01AI73896. S.C.C. was supported by an NSF graduate fellowship.

Publisher Copyright:
© 2016 Elsevier Inc.

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