title: Intracellular Action of a Secreted Peptide Required for Fungal Virulence.
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.
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Homer
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Diana K
authors.initials: DK
authors.lastname: Summers
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Alexi I
authors.initials: AI
authors.lastname: Goranov
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Starlynn C
authors.initials: SC
authors.lastname: Clarke
authors.affiliation: Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Darin L
authors.initials: DL
authors.lastname: Wiesner
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Jolene K
authors.initials: JK
authors.lastname: Diedrich
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Moresco
authors.affiliation: Department of Medicine, Duke University, Durham, NC 27710, USA.
authors.forename: Dena
authors.initials: D
authors.lastname: Toffaletti
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Upadhya
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Ippolito
authors.initials: I
authors.lastname: Caradonna
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Petnic
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Pessino
authors.affiliation: Genome Sequencing and Analysis Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Cuomo
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Lodge
authors.affiliation: Department of Medicine, Duke University, Durham, NC 27710, USA.
authors.forename: John
authors.initials: J
authors.lastname: Perfect
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.affiliation: Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Nielsen
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Craik
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: hitenmadhani@gmail.com.
authors.forename: Hiten D
authors.initials: HD
authors.lastname: Madhani
mesh_terms: D000818:Animals; D002473:Cell Wall / Q000502:physiology; D003453:Cryptococcosis / Q000378:metabolism / Q000382:microbiology*; D003455:Cryptococcus neoformans / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D004195:Disease Models, Animal; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008543:Melanins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D008581:Meningitis / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D010447:Peptide Hydrolases / Q000378:metabolism; D053038:Quorum Sensing; D011817:Rabbits; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D005656:Fungal Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008543:Melanins; D026901:Membrane Transport Proteins; D014157:Transcription Factors; D037521:Virulence Factors; C043912:peptide permease; D010447:Peptide Hydrolases