title: The SrkA Kinase Is Part of the SakA Mitogen-Activated Protein Kinase Interactome and Regulates Stress Responses and Development in Aspergillus nidulans.
abstract: Fungi and many other eukaryotes use specialized mitogen-activated protein kinases (MAPK) of the Hog1/p38 family to transduce environmental stress signals. In Aspergillus nidulans, the MAPK SakA and the transcription factor AtfA are components of a central multiple stress-signaling pathway that also regulates development. Here we characterize SrkA, a putative MAPK-activated protein kinase, as a novel component of this pathway. ΔsrkA and ΔsakA mutants share a derepressed sexual development phenotype. However, ΔsrkA mutants are not sensitive to oxidative stress, and in fact, srkA inactivation partially suppresses the sensitivity of ΔsakA mutant conidia to H2O2, tert-butyl-hydroperoxide (t-BOOH), and menadione. In the absence of stress, SrkA shows physical interaction with nonphosphorylated SakA in the cytosol. We show that H2O2 induces a drastic change in mitochondrial morphology consistent with a fission process and the relocalization of SrkA to nuclei and mitochondria, depending on the presence of SakA. SakA-SrkA nuclear interaction is also observed during normal asexual development in dormant spores. Using SakA and SrkA S-tag pulldown and purification studies coupled to mass spectrometry, we found that SakA interacts with SrkA, the stress MAPK MpkC, the PPT1-type phosphatase AN6892, and other proteins involved in cell cycle regulation, DNA damage response, mRNA stability and protein synthesis, mitochondrial function, and other stress-related responses. We propose that oxidative stress induces DNA damage and mitochondrial fission and that SakA and SrkA mediate cell cycle arrest and regulate mitochondrial function during stress. Our results provide new insights into the mechanisms by which SakA and SrkA regulate the remodelling of cell physiology during oxidative stress and development.
authors.affiliation: Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico.
authors.forename: Rafael
authors.initials: R
authors.lastname: Jaimes-Arroyo
authors.affiliation: Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico.
authors.forename: Fernando
authors.initials: F
authors.lastname: Lara-Rojas
authors.affiliation: Department of Biology, Maynooth University, National University of Ireland, Maynooth, County Kildare, Ireland.
authors.forename: Özgür
authors.initials: Ö
authors.lastname: Bayram
authors.affiliation: Department of Molecular Microbiology and Genetics, Georg August University, Göttingen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Valerius
authors.affiliation: Department of Molecular Microbiology and Genetics, Georg August University, Göttingen, Germany.
authors.forename: Gerhard H
authors.initials: GH
authors.lastname: Braus
authors.affiliation: Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico jaguirre@ifc.unam.mx.
authors.forename: Jesús
authors.initials: J
authors.lastname: Aguirre
mesh_terms: D001232:Aspergillus fumigatus / Q000235:genetics; D001233:Aspergillus nidulans / Q000235:genetics*; D005656:Fungal Proteins / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013172:Spores, Fungal / Q000235:genetics
chemical_list: D005656:Fungal Proteins; D006861:Hydrogen Peroxide; D020928:Mitogen-Activated Protein Kinases
references.citation: Microbiology. 1999 Feb;145 ( Pt 2):293-9
references.pmid: 10075411
references.citation: Mol Biol Cell. 2000 Apr;11(4):1169-81
references.pmid: 10749922
references.citation: Mol Biol Cell. 2001 Feb;12(2):407-19
references.pmid: 11179424
references.citation: Mol Microbiol. 2001 Mar;39(5):1166-73
references.pmid: 11251834
references.citation: Proc Natl Acad Sci U S A. 2001 May 8;98(10):5625-30
references.pmid: 11344302
references.citation: Mol Microbiol. 2002 Mar;43(5):1065-78
references.pmid: 11918796
references.citation: J Biol Chem. 2002 Sep 6;277(36):33411-21
references.pmid: 12080074
references.citation: Mol Microbiol. 2002 Aug;45(4):1153-63
references.pmid: 12180932
references.citation: Fungal Genet Biol. 2002 Oct;37(1):72-80
references.pmid: 12223191
references.citation: Genetics. 2002 Sep;162(1):73-87
references.pmid: 12242224
references.citation: Mol Genet Genomics. 2003 Feb;268(5):585-97
references.pmid: 12589433
references.citation: Nature. 2003 Apr 24;422(6934):859-68
references.pmid: 12712197
references.citation: Mol Microbiol. 2003 Nov;50(4):1241-55
references.pmid: 14622412
references.citation: Methods Enzymol. 1992;216:447-57
references.pmid: 1479914
references.citation: DNA Repair (Amst). 2004 Aug-Sep;3(8-9):959-67
references.pmid: 15279782
references.citation: Mol Microbiol. 2004 Sep;53(6):1743-56
references.pmid: 15341652
references.citation: Fungal Genet Biol. 2004 Nov;41(11):973-81
references.pmid: 15465386
references.citation: Fungal Genet Biol. 2004 Nov;41(11):982-97
references.pmid: 15465387
references.citation: Eukaryot Cell. 2004 Oct;3(5):1359-62
references.pmid: 15470263
references.citation: Mol Cell. 2005 Jan 7;17(1):49-59
references.pmid: 15629716
references.citation: Trends Microbiol. 2005 Mar;13(3):111-8
references.pmid: 15737729
references.citation: Mol Microbiol. 2005 Jun;56(5):1246-61
references.pmid: 15882418
references.citation: Mol Genet Genomics. 2005 Jun;273(5):433-9
references.pmid: 15887030
references.citation: Mol Biol Cell. 2006 Mar;17(3):1472-82
references.pmid: 16381815
references.citation: Genetics. 2006 Mar;172(3):1557-66
references.pmid: 16387870
references.citation: Mol Microbiol. 2006 Feb;59(3):753-64
references.pmid: 16420349
references.citation: Eukaryot Cell. 2006 Nov;5(11):1934-40
references.pmid: 16998074
references.citation: Mol Cell Biol. 2007 Jan;27(1):170-81
references.pmid: 17030606
references.citation: Eukaryot Cell. 2006 Oct;5(10):1688-704
references.pmid: 17030995
references.citation: Plant Cell. 2006 Oct;18(10):2807-21
references.pmid: 17041146
references.citation: Nat Cell Biol. 2007 Jan;9(1):99-105
references.pmid: 17173038
references.citation: Eukaryot Cell. 2007 Mar;6(3):521-32
references.pmid: 17220467
references.citation: Fungal Genet Biol. 2007 Sep;44(9):886-95
references.pmid: 17258477
references.citation: Eukaryot Cell. 2007 Sep;6(9):1570-83
references.pmid: 17630329
references.citation: Curr Genet. 2008 Mar;53(3):163-74
references.pmid: 18188569
references.citation: Mol Biol Cell. 2008 Apr;19(4):1670-9
references.pmid: 18272791
references.citation: Science. 2008 Jun 13;320(5882):1504-6
references.pmid: 18556559
references.citation: Eukaryot Cell. 2008 Aug;7(8):1352-61
references.pmid: 18567788
references.citation: Mol Cell. 2008 Sep 5;31(5):722-36
references.pmid: 18775331
references.citation: Eukaryot Cell. 2009 Apr;8(4):573-85
references.pmid: 19181872
references.citation: Fungal Genet Biol. 2009 Nov;46(11):868-78
references.pmid: 19596074
references.citation: Mol Cell Biol. 1991 Jan;11(1):38-46
references.pmid: 1986232
references.citation: Eukaryot Cell. 2010 May;9(5):831-3
references.pmid: 20363899
references.citation: Mol Microbiol. 2010 Jun 1;76(5):1191-204
references.pmid: 20398212
references.citation: FEMS Yeast Res. 2010 Jun;10(4):441-51
references.pmid: 20402792
references.citation: Eukaryot Cell. 2010 Jul;9(7):1039-48
references.pmid: 20495057
references.citation: Free Radic Biol Med. 2010 Nov 15;49(9):1342-53
references.pmid: 20696238
references.citation: J Microbiol. 2010 Dec;48(6):885-7
references.pmid: 21221952
references.citation: Mol Microbiol. 2011 Apr;80(2):436-54
references.pmid: 21320182
references.citation: PLoS One. 2011 Apr 13;6(4):e18769
references.pmid: 21533251
references.citation: Biotechnol Bioeng. 2011 Nov;108(11):2705-15
references.pmid: 21618477
references.citation: J Microbiol. 2011 Jun;49(3):418-30
references.pmid: 21717328
references.citation: Mol Biol Cell. 2012 Jan;23(2):268-83
references.pmid: 22090345
references.citation: EMBO J. 2012 Feb 1;31(3):563-75
references.pmid: 22139357
references.citation: PLoS Genet. 2011 Dec;7(12):e1002387
references.pmid: 22144909
references.citation: Fungal Genet Biol. 2012 Feb;49(2):180-8
references.pmid: 22240319
references.citation: Mol Plant Microbe Interact. 2012 Jun;25(6):802-16
references.pmid: 22352714
references.citation: J Proteomics. 2012 Jul 16;75(13):4038-49
references.pmid: 22634043
references.citation: Mol Cell. 2012 Aug 24;47(4):547-57
references.pmid: 22748923
references.citation: PLoS Genet. 2012;8(7):e1002816
references.pmid: 22829779
references.citation: Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):14918-23
references.pmid: 22927395
references.citation: Cell Biosci. 2012 Aug 29;2(1):30
references.pmid: 22932476
references.citation: Mol Biol Cell. 2012 Nov;23(21):4286-96
references.pmid: 22956768
references.citation: J Biol Chem. 2012 Dec 28;287(53):44221-33
references.pmid: 23105103
references.citation: Proc Natl Acad Sci U S A. 2013 Feb 19;110(8):3179-84
references.pmid: 23382235
references.citation: PLoS One. 2013;8(2):e55879
references.pmid: 23418468
references.citation: PLoS One. 2013;8(2):e56486
references.pmid: 23418575
references.citation: Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):4840-5
references.pmid: 23487796
references.citation: PLoS One. 2013;8(3):e58008
references.pmid: 23505451
references.citation: J Theor Biol. 1990 Jan 23;142(2):201-21
references.pmid: 2352433
references.citation: Mol Plant Microbe Interact. 2013 Dec;26(12):1378-94
references.pmid: 23945004
references.citation: Nucleic Acids Res. 2014 Jan;42(Database issue):D705-10
references.pmid: 24194595
references.citation: Genetics. 2014 Mar;196(3):729-44
references.pmid: 24407906
references.citation: Aging (Albany NY). 2014 Jun;6(6):481-95
references.pmid: 24934860
references.citation: Genes Dev. 2014 Sep 15;28(18):1977-82
references.pmid: 25189701
references.citation: Int J Med Microbiol. 2015 Jan;305(1):65-74
references.pmid: 25466206
references.citation: Mol Cell. 2015 Feb 5;57(3):537-51
references.pmid: 25658205
references.citation: Med Mycol. 2006 Sep 1;44(Supplement_1):S101-S107
references.pmid: 30408892
references.citation: Genetics. 1965 Jul;52(1):217-32
references.pmid: 5857597
references.citation: Biochemistry. 1995 Apr 25;34(16):5569-76
references.pmid: 7727418
references.citation: Mol Cell Biol. 1996 Jun;16(6):2870-7
references.pmid: 8649397
references.citation: Genes Dev. 1996 Sep 15;10(18):2276-88
references.pmid: 8824587
references.citation: J Biol Chem. 1996 Dec 27;271(52):33678-85
references.pmid: 8969238
references.citation: Genetics. 1996 Dec;144(4):1463-70
references.pmid: 8978035
references.citation: EMBO J. 1997 Jan 2;16(1):182-92
references.pmid: 9009279
references.citation: J Bacteriol. 1998 Sep;180(17):4460-5
references.pmid: 9721283