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05 04, 2020;10 (5): 1521-1539.

DAF-16 and SMK-1 Contribute to Innate Immunity During Adulthood in .

Daniel R McHugh, Elena Koumis, Paul Jacob, Jennifer Goldfarb, Michelle Schlaubitz-Garcia, Safae Bennani, Paul Regan, Prem Patel, Matthew J Youngman
Author Information
  1. Daniel R McHugh: Department of Biology, Villanova University, Villanova, PA 19085.
  2. Elena Koumis: Department of Biology, Villanova University, Villanova, PA 19085.
  3. Paul Jacob: Department of Biology, Villanova University, Villanova, PA 19085.
  4. Jennifer Goldfarb: Department of Biology, Villanova University, Villanova, PA 19085.
  5. Michelle Schlaubitz-Garcia: Department of Biology, Villanova University, Villanova, PA 19085.
  6. Safae Bennani: Department of Biology, Villanova University, Villanova, PA 19085.
  7. Paul Regan: Department of Biology, Villanova University, Villanova, PA 19085.
  8. Prem Patel: Department of Biology, Villanova University, Villanova, PA 19085.
  9. Matthew J Youngman: Department of Biology, Villanova University, Villanova, PA 19085 matthew.youngman@villanova.edu. ORCID
PMID: 32161087 DOI: 10.1534/g3.120.401166

Abstract

Aging is accompanied by a progressive decline in immune function termed "immunosenescence". Deficient surveillance coupled with the impaired function of immune cells compromises host defense in older animals. The dynamic activity of regulatory modules that control immunity appears to underlie age-dependent modifications to the immune system. In the roundworm levels of PMK-1 p38 MAP kinase diminish over time, reducing the expression of immune effectors that clear bacterial pathogens. Along with the PMK-1 pathway, innate immunity in is regulated by the insulin signaling pathway. Here we asked whether DAF-16, a Forkhead box (FOXO) transcription factor whose activity is inhibited by insulin signaling, plays a role in host defense later in life. While in younger DAF-16 is inactive unless stimulated by environmental insults, we found that even in the absence of acute stress the transcriptional activity of DAF-16 increases in an age-dependent manner. Beginning in the reproductive phase of adulthood, DAF-16 upregulates a subset of its transcriptional targets, including genes required to kill ingested microbes. Accordingly, DAF-16 has little to no role in larval immunity, but functions specifically during adulthood to confer resistance to bacterial pathogens. We found that DAF-16-mediated immunity in adults requires SMK-1, a regulatory subunit of the PP4 protein phosphatase complex. Our data suggest that as the function of one branch of the innate immune system of (PMK-1) declines over time, DAF-16-mediated immunity ramps up to become the predominant means of protecting adults from infection, thus reconfiguring immunity later in life.

Keywords

C. elegans DAF-16 SMK-1 aging innate immunity

References

  1. Genes Dev. 2007 Nov 15;21(22):2976-94 [PMID: 18006689]
  2. Genetics. 2015 May;200(1):167-84 [PMID: 25762526]
  3. Cell. 2006 Mar 10;124(5):1039-53 [PMID: 16530049]
  4. Aging Cell. 2003 Apr;2(2):111-21 [PMID: 12882324]
  5. Science. 1997 Aug 15;277(5328):942-6 [PMID: 9252323]
  6. Nature. 2003 Jul 17;424(6946):277-83 [PMID: 12845331]
  7. J Gerontol A Biol Sci Med Sci. 2006 May;61(5):444-60 [PMID: 16720740]
  8. PLoS Genet. 2008 Nov;4(11):e1000273 [PMID: 19023415]
  9. Dev Comp Immunol. 1999 Jun-Jul;23(4-5):267-79 [PMID: 10426421]
  10. Genetics. 2008 Feb;178(2):903-18 [PMID: 18245330]
  11. J Immunol. 2013 Feb 15;190(4):1746-57 [PMID: 23319733]
  12. Science. 2004 Mar 26;303(5666):2011-5 [PMID: 14976264]
  13. Curr Biol. 2001 Dec 11;11(24):1950-7 [PMID: 11747821]
  14. Genes Dev. 2003 Aug 1;17(15):1882-93 [PMID: 12869585]
  15. Aging Cell. 2012 Aug;11(4):659-67 [PMID: 22554143]
  16. Autophagy. 2016;12(2):261-72 [PMID: 26671266]
  17. Aging Cell. 2009 Jun;8(3):277-87 [PMID: 19627267]
  18. Science. 2002 Oct 25;298(5594):830-4 [PMID: 12399591]
  19. PLoS Pathog. 2008 Oct;4(10):e1000175 [PMID: 18927620]
  20. Proc Natl Acad Sci U S A. 2014 May 20;111(20):7313-8 [PMID: 24711418]
  21. Nat Immunol. 2008 Dec;9(12):1415-24 [PMID: 18854822]
  22. Genetics. 1996 Jul;143(3):1207-18 [PMID: 8807294]
  23. Nat Struct Mol Biol. 2010 Mar;17(3):365-72 [PMID: 20154705]
  24. Nature. 1994 Nov 10;372(6502):182-6 [PMID: 7969452]
  25. Mol Cell Biol. 2007 Aug;27(15):5544-53 [PMID: 17526726]
  26. Cell Metab. 2009 Nov;10(5):379-91 [PMID: 19883616]
  27. Aging Cell. 2019 Jun;18(3):e12896 [PMID: 30773782]
  28. FEBS Lett. 2005 Jun 13;579(15):3278-86 [PMID: 15913612]
  29. J Immunol. 2017 Mar 1;198(5):1910-1920 [PMID: 28115529]
  30. Genetics. 2015 Oct;201(2):613-29 [PMID: 26219299]
  31. Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):715-20 [PMID: 9892699]
  32. mBio. 2017 May 30;8(3): [PMID: 28559483]
  33. Nature. 1993 Dec 2;366(6454):461-4 [PMID: 8247153]
  34. PLoS Genet. 2011 Apr;7(4):e1002047 [PMID: 21533182]
  35. PLoS One. 2011;6(9):e24619 [PMID: 21931778]
  36. FEMS Microbiol Lett. 2004 May 15;234(2):281-7 [PMID: 15135534]
  37. Genetics. 2002 Jul;161(3):1101-12 [PMID: 12136014]
  38. J Immunol. 2015 Sep 15;195(6):2624-32 [PMID: 26246142]
  39. Science. 2001 Apr 6;292(5514):107-10 [PMID: 11292875]
  40. Genes Dev. 2009 Feb 1;23(3):359-72 [PMID: 19204120]
  41. Science. 2003 Jun 20;300(5627):1921 [PMID: 12817143]
  42. J Cell Biol. 2007 Oct 8;179(1):41-52 [PMID: 17908915]
  43. EMBO J. 2012 May 16;31(10):2403-15 [PMID: 22491012]
  44. PLoS Biol. 2008 Sep 30;6(9):e233 [PMID: 18828672]
  45. Redox Biol. 2018 Sep;18:191-199 [PMID: 30031267]
  46. Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):14914-9 [PMID: 19706382]
  47. Philos Trans R Soc Lond B Biol Sci. 2016 May 26;371(1695): [PMID: 27160601]
  48. Curr Biol. 2002 Jul 23;12(14):1209-14 [PMID: 12176330]
  49. Nat Genet. 2001 Jun;28(2):139-45 [PMID: 11381260]
  50. Science. 2003 Apr 25;300(5619):644-7 [PMID: 12690206]
  51. J Biol Chem. 2017 Feb 3;292(5):1762-1772 [PMID: 28011639]
  52. J Biol Chem. 2009 Dec 18;284(51):35580-7 [PMID: 19858203]
  53. Aging Cell. 2008 Mar;7(2):225-36 [PMID: 18221416]
  54. Proc Natl Acad Sci U S A. 2004 May 25;101(21):8084-9 [PMID: 15141086]
  55. Cell. 2013 Aug 1;154(3):676-690 [PMID: 23911329]
  56. Genetics. 1974 May;77(1):71-94 [PMID: 4366476]
  57. Genetics. 2017 Sep;207(1):83-101 [PMID: 28696216]
  58. PLoS Pathog. 2012;8(4):e1002673 [PMID: 22577361]
  59. Cell Metab. 2006 Dec;4(6):429-40 [PMID: 17141627]
  60. Vaccine. 2000 Feb 25;18(16):1717-20 [PMID: 10689155]
  61. Science. 2002 Jul 26;297(5581):623-6 [PMID: 12142542]
  62. Aquat Toxicol. 2005 Sep 30;74(4):320-32 [PMID: 16040138]
  63. Immunity. 2019 Apr 16;50(4):924-940 [PMID: 30995507]
  64. Int J Mol Med. 2005 Aug;16(2):237-43 [PMID: 16012755]
  65. Nat Cell Biol. 2014 Dec;16(12):1168-1179 [PMID: 25419847]
  66. Cell. 2006 Jun 16;125(6):1165-77 [PMID: 16777605]
  67. J Biol Inorg Chem. 2011 Feb;16(2):267-74 [PMID: 21057967]
  68. PLoS One. 2013 Jul 16;8(7):e68804 [PMID: 23874770]
  69. Cell. 2012 Jan 20;148(1-2):322-34 [PMID: 22265419]
  70. Methods. 2001 Dec;25(4):402-8 [PMID: 11846609]
  71. Nature. 2010 Jul 22;466(7305):498-502 [PMID: 20613724]
  72. PLoS Genet. 2011 May;7(5):e1002082 [PMID: 21625567]
  73. Curr Biol. 2001 Dec 11;11(24):1975-80 [PMID: 11747825]
  74. Mol Cell Biol. 2011 Feb;31(3):507-16 [PMID: 21135129]
  75. PLoS One. 2011;6(5):e19055 [PMID: 21602919]
  76. Longev Healthspan. 2014 Apr 23;3:5 [PMID: 24834345]
  77. Cell Biosci. 2014 May 07;4:25 [PMID: 24904742]
  78. Biol Pharm Bull. 2009 Dec;32(12):1973-7 [PMID: 19952414]
  79. Science. 2003 May 16;300(5622):1142-5 [PMID: 12750521]
  80. BMC Biol. 2006 Feb 03;4:1 [PMID: 16457721]
  81. PLoS Genet. 2006 Nov 10;2(11):e183 [PMID: 17096597]
  82. Nature. 2002 Oct 24;419(6909):808-14 [PMID: 12397350]
  83. Cell. 2013 Jun 20;153(7):1435-47 [PMID: 23791175]
  84. Science. 2005 May 20;308(5725):1181-4 [PMID: 15905404]
  85. Trends Endocrinol Metab. 2012 Dec;23(12):637-44 [PMID: 22939742]
  86. Nat Immunol. 2009 Mar;10(3):249-56 [PMID: 19198592]
  87. Cell. 2003 Nov 14;115(4):489-502 [PMID: 14622602]
  88. Aging (Albany NY). 2016 Apr;8(4):777-95 [PMID: 27053445]
  89. Exp Gerontol. 2006 Oct;41(10):928-34 [PMID: 16839734]
  90. PLoS One. 2006 Dec 20;1:e77 [PMID: 17183709]

Grants

  1. P40 OD010440/NIH HHS

MeSH Term

Animals
Caenorhabditis elegans
Caenorhabditis elegans Proteins
Forkhead Transcription Factors
Gene Expression Regulation
Immunity, Innate
Phosphoprotein Phosphatases

Chemicals

Caenorhabditis elegans Proteins
Forkhead Transcription Factors
daf-16 protein, C elegans
Phosphoprotein Phosphatases
SMK-1 protein, C elegans
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Links to CNCB-NGDC Resources

GEN: GEND000162 (Genome-wide profiling of age-dependent changes in gene expression between L4 larvae and Day 6 adult Caenorhabditis elegans)

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