title: Canonical heterotrimeric G proteins regulating mating and virulence of Cryptococcus neoformans.
abstract: Perturbation of pheromone signaling modulates not only mating but also virulence in Cryptococcus neoformans, an opportunistic human pathogen known to encode three Galpha, one Gbeta, and two Ggamma subunit proteins. We have found that Galphas Gpa2 and Gpa3 exhibit shared and distinct roles in regulating pheromone responses and mating. Gpa2 interacted with the pheromone receptor homolog Ste3alpha, Gbeta subunit Gpb1, and RGS protein Crg1. Crg1 also exhibited in vitro GAP activity toward Gpa2. These findings suggest that Gpa2 regulates mating through a conserved signaling mechanism. Moreover, we found that Ggammas Gpg1 and Gpg2 both regulate pheromone responses and mating. gpg1 mutants were attenuated in mating, and gpg2 mutants were sterile. Finally, although gpa2, gpa3, gpg1, gpg2, and gpg1 gpg2 mutants were fully virulent, gpa2 gpa3 mutants were attenuated for virulence in a murine model. Our study reveals a conserved but distinct signaling mechanism by two Galpha, one Gbeta, and two Ggamma proteins for pheromone responses, mating, and virulence in Cryptococcus neoformans, and it also reiterates that the link between mating and virulence is not due to mating per se but rather to certain mating-pathway components that encode additional functions promoting virulence.
authors: Department of Pediatrics,The Research Institute for Children, Louisiana State University Health Sciences Center, New Orleans, LA 70118, USA.
authors: Lie
authors: L
authors: Li
authors: Gui
authors: G
authors: Shen
authors: Zheng-Guang
authors: ZG
authors: Zhang
authors: Yan-Li
authors: YL
authors: Wang
authors: Jill K
authors: JK
authors: Thompson
authors: Ping
authors: P
authors: Wang
mesh_terms: D000818:Animals; D003453:Cryptococcosis / Q000378:metabolism / Q000473:pathology; D003455:Cryptococcus neoformans / Q000472:pathogenicity* / Q000502:physiology*; D015966:Gene Expression Regulation, Fungal; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010675:Pheromones / Q000378:metabolism; D011485:Protein Binding; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D014774:Virulence
chemical_list: D010675:Pheromones; D021122:Protein Subunits; D020962:Heterotrimeric GTP-Binding Proteins
references: Curr Opin Microbiol. 1999 Aug;2(4):358-62
references: 10458985
references: Mol Cell Biol. 2000 Jan;20(1):352-62
references: 10594037
references: Infect Immun. 1992 Feb;60(2):602-5
references: 1730495
references: J Biol Chem. 1997 Aug 15;272(33):20321-3
references: 9252333
references: Curr Genet. 2004 Nov;46(5):247-55
references: 15503029
references: Mol Microbiol. 1999 Sep;33(5):904-18
references: 10476026
references: Mol Cell Biol. 1990 Jan;10(1):217-22
references: 2104659
references: Mol Biol Cell. 2006 Feb;17(2):667-79
references: 16291861
references: Mol Microbiol. 2001 Apr;40(1):200-13
references: 11298287
references: Infect Immun. 1993 Oct;61(10):4446-51
references: 8406836
references: Eukaryot Cell. 2002 Jun;1(3):378-90
references: 12455986
references: Microbiol Mol Biol Rev. 2000 Dec;64(4):746-85
references: 11104818
references: Genetics. 2004 Mar;166(3):1229-40
references: 15082543
references: Eukaryot Cell. 2004 Jun;3(3):610-9
references: 15189983
references: Infect Immun. 2003 Sep;71(9):4953-60
references: 12933837
references: Mol Biol Cell. 2007 Sep;18(9):3237-49
references: 17581859
references: J Exp Med. 2000 Mar 6;191(5):871-82
references: 10704467
references: Eukaryot Cell. 2002 Feb;1(1):75-84
references: 12455973
references: Med Mycol. 2001 Feb;39(1):151-4
references: 11270405
references: Genes Dev. 1997 Dec 1;11(23):3206-17
references: 9389652
references: Eukaryot Cell. 2002 Apr;1(2):257-72
references: 12455960
references: EMBO J. 1997 Dec 1;16(23):7008-18
references: 9384580
references: J Biol Chem. 2000 Oct 27;275(43):33497-503
references: 10942773
references: Infect Dis Clin North Am. 2006 Sep;20(3):507-44, v-vi
references: 16984867
references: Eukaryot Cell. 2003 Oct;2(5):1036-45
references: 14555486
references: Eukaryot Cell. 2005 Mar;4(3):495-503
references: 15755912
references: EMBO J. 1997 Apr 15;16(8):1934-42
references: 9155019
references: EMBO J. 1999 Oct 15;18(20):5577-91
references: 10523302
references: Clin Microbiol Rev. 1995 Oct;8(4):515-48
references: 8665468
references: Mol Cell Biol. 1993 Jan;13(1):1-8
references: 8417317
references: EMBO J. 1998 Jun 15;17(12):3326-41
references: 9628870
references: Annu Rev Genet. 2002;36:557-615
references: 12429703
references: Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):14122-7
references: 11038529
references: Eukaryot Cell. 2002 Aug;1(4):634-42
references: 12456011
references: J Biol Chem. 2006 Oct 27;281(43):32596-605
references: 16950773
references: EMBO Rep. 2001 Jun;2(6):511-8
references: 11415984
references: Mol Microbiol. 2003 Jul;49(2):469-85
references: 12828643
references: Fungal Genet Biol. 1998 Oct;25(1):1-14
references: 9806801
references: Eukaryot Cell. 2005 Feb;4(2):365-78
references: 15701799
references: Eukaryot Cell. 2002 Jun;1(3):432-9
references: 12455991
references: Infect Immun. 2003 Sep;71(9):4831-41
references: 12933823
references: Genetics. 1996 Dec;144(4):1425-36
references: 8978031
references: Mol Cell Biol. 2001 May;21(9):3179-91
references: 11287622
references: Biochemistry. 1998 Apr 7;37(14):4815-22
references: 9537998
references: Fungal Genet Biol. 2000 Apr;29(3):153-63
references: 10882532
references: Plant Cell. 1997 Nov;9(11):1973-83
references: 9401122
references: Cell. 1989 Feb 10;56(3):467-77
references: 2536595
references: Eukaryot Cell. 2004 Dec;3(6):1476-91
references: 15590822
references: Mol Plant Microbe Interact. 1997 Dec;10(9):1075-86
references: 9390422
references: Eukaryot Cell. 2004 Aug;3(4):1028-35
references: 15302835
references: Adv Genet. 2007;57:143-73
references: 17352904
references: Science. 2005 Feb 25;307(5713):1321-4
references: 15653466