title: Graded Proteasome Dysfunction in Caenorhabditis elegans Activates an Adaptive Response Involving the Conserved SKN-1 and ELT-2 Transcription Factors and the Autophagy-Lysosome Pathway.
abstract: The maintenance of cellular proteins in a biologically active and structurally stable state is a vital endeavor involving multiple cellular pathways. One such pathway is the ubiquitin-proteasome system that represents a major route for protein degradation, and reductions in this pathway usually have adverse effects on the health of cells and tissues. Here, we demonstrate that loss-of-function mutants of the Caenorhabditis elegans proteasome subunit, RPN-10, exhibit moderate proteasome dysfunction and unexpectedly develop both increased longevity and enhanced resistance to multiple threats to the proteome, including heat, oxidative stress, and the presence of aggregation prone proteins. The rpn-10 mutant animals survive through the activation of compensatory mechanisms regulated by the conserved SKN-1/Nrf2 and ELT-2/GATA transcription factors that mediate the increased expression of genes encoding proteasome subunits as well as those mediating oxidative- and heat-stress responses. Additionally, we find that the rpn-10 mutant also shows enhanced activity of the autophagy-lysosome pathway as evidenced by increased expression of the multiple autophagy genes including atg-16.2, lgg-1, and bec-1, and also by an increase in GFP::LGG-1 puncta. Consistent with a critical role for this pathway, the enhanced resistance of the rpn-10 mutant to aggregation prone proteins depends on autophagy genes atg-13, atg-16.2, and prmt-1. Furthermore, the rpn-10 mutant is particularly sensitive to the inhibition of lysosome activity via either RNAi or chemical means. We also find that the rpn-10 mutant shows a reduction in the numbers of intestinal lysosomes, and that the elt-2 gene also plays a novel and vital role in controlling the production of functional lysosomes by the intestine. Overall, these experiments suggest that moderate proteasome dysfunction could be leveraged to improve protein homeostasis and organismal health and longevity, and that the rpn-10 mutant provides a unique platform to explore these possibilities.
authors.affiliation: Division of Geriatric Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Keith
authors.affiliation: Division of Geriatrics, Gerontology, and Palliative Medicine, Department of Medicine, The University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas, United States of America.|Center for Healthy Aging, Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas, United States of America.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Maddux
authors.affiliation: Division of Geriatrics, Gerontology, and Palliative Medicine, Department of Medicine, The University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas, United States of America.|Center for Healthy Aging, Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas, United States of America.
authors.forename: Yayu
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Division of Geriatrics, Gerontology, and Palliative Medicine, Department of Medicine, The University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas, United States of America.|Center for Healthy Aging, Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas, United States of America.
authors.forename: Meghna N
authors.initials: MN
authors.lastname: Chinchankar
authors.affiliation: Division of Geriatric Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Annabel A
authors.initials: AA
authors.lastname: Ferguson
authors.affiliation: Rangos Research Center, Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Arjumand
authors.initials: A
authors.lastname: Ghazi
authors.affiliation: Division of Geriatrics, Gerontology, and Palliative Medicine, Department of Medicine, The University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas, United States of America.|Center for Healthy Aging, Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, Texas, United States of America.|San Antonio GRECC, South Texas VA Healthcare System, San Antonio, Texas, United States of America.
authors.forename: Alfred L
authors.initials: AL
authors.lastname: Fisher
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D001343:Autophagy; D017173:Caenorhabditis elegans / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D017124:Conserved Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004064:Digestive System / Q000378:metabolism; D050980:GATA Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D018869:Heat-Shock Response / Q000235:genetics; D008247:Lysosomes / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017510:Protein Folding; D021122:Protein Subunits / Q000378:metabolism; D017423:Sequence Analysis, RNA; D013312:Stress, Physiological; D014157:Transcription Factors / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; C094134:ELT-2 protein, C elegans; D050980:GATA Transcription Factors; D021122:Protein Subunits; D014157:Transcription Factors; D025801:Ubiquitin; C073702:skn-1 protein, C elegans; D046988:Proteasome Endopeptidase Complex
references.citation: Nature. 2007 Jun 14;447(7146):859-63
references.pmid: 17568747
references.citation: Methods Enzymol. 2002;353:497-505
references.pmid: 12078522
references.citation: J Biol Chem. 2005 Dec 2;280(48):40282-92
references.pmid: 16192271
references.citation: J Biol Chem. 1999 Feb 5;274(6):3363-71
references.pmid: 9920878
references.citation: Aging Cell. 2009 Sep;8(5):524-41
references.pmid: 19575768
references.citation: Science. 2003 Sep 5;301(5638):1387-91
references.pmid: 12958363
references.citation: Mol Biol Cell. 2006 Dec;17(12):5356-71
references.pmid: 17050737
references.citation: Biochem Biophys Res Commun. 1993 Aug 31;195(1):393-9
references.pmid: 8395831
references.citation: Mol Cell Biol. 2010 Jun;30(11):2651-67
references.pmid: 20351174
references.citation: Curr Biol. 2014 Jul 21;24(14):1573-1583
references.pmid: 24998528
references.citation: J Neurochem. 2003 Jul;86(2):489-97
references.pmid: 12871590
references.citation: Cell Stress Chaperones. 1999 Dec;4(4):235-42
references.pmid: 10590837
references.citation: Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10417-22
references.pmid: 12122205
references.citation: Biochem J. 2012 Feb 1;441(3):927-36
references.pmid: 22004789
references.citation: Mol Cell. 2007 Sep 7;27(5):731-44
references.pmid: 17803938
references.citation: Proc Natl Acad Sci U S A. 2008 May 13;105(19):7094-9
references.pmid: 18467495
references.citation: Mol Cell. 2006 Sep 15;23(6):875-85
references.pmid: 16973439
references.citation: Mol Cell. 2001 Mar;7(3):627-37
references.pmid: 11463387
references.citation: J Biol Chem. 1997 Nov 7;272(45):28557-62
references.pmid: 9353319
references.citation: Genes Dev. 2003 Aug 1;17(15):1882-93
references.pmid: 12869585
references.citation: J Biol Chem. 2015 Apr 10;290(15):9455-64
references.pmid: 25713068
references.citation: J Neurochem. 2001 Jul;78(1):32-41
references.pmid: 11432971
references.citation: Methods. 2003 Aug;30(4):313-21
references.pmid: 12828945
references.citation: Aging Cell. 2009 Jun;8(3):258-69
references.pmid: 19627265
references.citation: BMC Bioinformatics. 2010 Feb 18;11:94
references.pmid: 20167110
references.citation: Biol Chem. 2002 Jul-Aug;383(7-8):1263-6
references.pmid: 12437114
references.citation: Nature. 2002 Sep 26;419(6905):403-7
references.pmid: 12353037
references.citation: Nat Biotechnol. 2010 Aug;28(8):868-73
references.pmid: 20639865
references.citation: Nat Protoc. 2009;4(1):44-57
references.pmid: 19131956
references.citation: Mech Ageing Dev. 2001 Mar;122(3):235-54
references.pmid: 11311314
references.citation: FASEB J. 2015 Feb;29(2):611-22
references.pmid: 25395451
references.citation: J Neurochem. 2004 Jul;90(1):19-28
references.pmid: 15198663
references.citation: Dev Biol. 2007 Feb 15;302(2):627-45
references.pmid: 17113066
references.citation: Biochemistry. 2008 Jan 22;47(3):859-69
references.pmid: 18154321
references.citation: Mol Cell. 2013 Sep 26;51(6):819-28
references.pmid: 24035499
references.citation: Mol Cell Biol. 2009 May;29(10):2704-15
references.pmid: 19273594
references.citation: Curr Biol. 2005 Jul 12;15(13):1249-54
references.pmid: 16005300
references.citation: Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2898-903
references.pmid: 10717003
references.citation: Dev Biol. 2009 Mar 15;327(2):551-65
references.pmid: 19111532
references.citation: Exp Cell Res. 1976 Jul;100(2):276-80
references.pmid: 939253
references.citation: Genes Dev. 1998 Jul 1;12(13):1962-74
references.pmid: 9649501
references.citation: Neuron. 2001 Jan;29(1):15-32
references.pmid: 11182078
references.citation: Cell. 2012 Aug 17;150(4):855-66
references.pmid: 22901814
references.citation: Genes Dev. 1998 Aug 1;12(15):2263-8
references.pmid: 9694792
references.citation: Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):5947-52
references.pmid: 17392428
references.citation: Proc Natl Acad Sci U S A. 2012 Jun 26;109(26):10587-92
references.pmid: 22645345
references.citation: Nature. 2012 Sep 13;489(7415):263-8
references.pmid: 22922647
references.citation: EMBO Rep. 2001 Sep;2(9):821-8
references.pmid: 11559592
references.citation: Mol Cell. 2013 Nov 7;52(3):421-33
references.pmid: 24140420
references.citation: J Biol Chem. 1997 Apr 4;272(14):9086-92
references.pmid: 9083035
references.citation: Science. 2008 Feb 15;319(5865):916-9
references.pmid: 18276881
references.citation: Proc Natl Acad Sci U S A. 2013 Sep 10;110(37):15067-72
references.pmid: 23980181
references.citation: Genes Dev. 2005 Oct 1;19(19):2278-83
references.pmid: 16166371
references.citation: Mol Cell. 2011 Oct 21;44(2):325-40
references.pmid: 21906983
references.citation: Nat Biotechnol. 2003 Aug;21(8):921-6
references.pmid: 12872131
references.citation: Nature. 2008 May 22;453(7194):548-52
references.pmid: 18497827
references.citation: J Biol Chem. 2010 Oct 29;285(44):33992-4003
references.pmid: 20739285
references.citation: BMC Dev Biol. 2008 Dec 30;8:119
references.pmid: 19116030
references.citation: Mol Cell. 2015 Jun 18;58(6):1053-66
references.pmid: 26004230
references.citation: Mol Biochem Parasitol. 2005 Feb;139(2):197-203
references.pmid: 15664654
references.citation: Biochim Biophys Acta. 2014 Jan;1843(1):13-25
references.pmid: 23994620
references.citation: Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):14914-9
references.pmid: 19706382
references.citation: Autophagy. 2015;11(1):9-27
references.pmid: 25569839
references.citation: Genetics. 2011 Apr;187(4):1235-40
references.pmid: 21288877
references.citation: BMC Bioinformatics. 2011 Aug 04;12:323
references.pmid: 21816040
references.citation: J Vis Exp. 2010 Aug 23;(42):
references.pmid: 20811328
references.citation: J Cell Sci. 2006 May 15;119(Pt 10):1977-84
references.pmid: 16687735
references.citation: J Biol Chem. 2004 Nov 5;279(45):46723-32
references.pmid: 15328361
references.citation: Science. 2002 Oct 18;298(5593):611-5
references.pmid: 12183636
references.citation: BMC Mol Biol. 2008 Jan 22;9:9
references.pmid: 18211699
references.citation: J Biol Chem. 1995 Feb 3;270(5):2344-51
references.pmid: 7836468
references.citation: J Biol Chem. 1996 Jun 28;271(26):15504-9
references.pmid: 8663134
references.citation: Prog Mol Biol Transl Sci. 2012;109:227-48
references.pmid: 22727423
references.citation: Genetics. 2007 Dec;177(4):2039-62
references.pmid: 18073423
references.citation: Genes Cells. 2005 Jul;10(7):693-704
references.pmid: 15966900
references.citation: Blood. 2010 Jul 8;116(1):85-96
references.pmid: 20410505
references.citation: BMC Dev Biol. 2008 May 09;8:51
references.pmid: 18471277
references.citation: Mol Cell. 2005 Feb 4;17(3):351-65
references.pmid: 15694337
references.citation: Cell Metab. 2012 Jan 4;15(1):88-99
references.pmid: 22225878
references.citation: Nature. 2008 May 22;453(7194):481-8
references.pmid: 18497817
references.citation: Nucleic Acids Res. 1998 Apr 1;26(7):1621-7
references.pmid: 9512531
references.citation: Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):14912-7
references.pmid: 22927396
references.citation: F1000Prime Rep. 2014 Feb 03;6:7
references.pmid: 24592319
references.citation: Proc Natl Acad Sci U S A. 2006 Sep 19;103(38):14086-91
references.pmid: 16968778
references.citation: PLoS Biol. 2007 Sep;5(9):e237
references.pmid: 17850180
references.citation: Autophagy. 2009 Jul;5(5):608-15
references.pmid: 19377305
references.citation: Cell Rep. 2015 May 19;11(7):1123-33
references.pmid: 25959815
references.citation: PLoS Genet. 2013 Apr;9(4):e1003466
references.pmid: 23637632
references.citation: Cell. 2015 May 7;161(4):919-32
references.pmid: 25957690
references.citation: Nat Biotechnol. 2008 Mar;26(3):317-25
references.pmid: 18278033
references.citation: J Exp Biol. 2013 Feb 15;216(Pt 4):543-53
references.pmid: 23038734
references.citation: Mol Cell. 2009 Dec 11;36(5):794-804
references.pmid: 20005843
references.citation: Cell Stress Chaperones. 2001 Jan;6(1):6-15
references.pmid: 11525245
references.citation: Genes Dev. 2007 Sep 1;21(17):2161-71
references.pmid: 17785524
references.citation: Mol Cell. 2003 Jan;11(1):69-78
references.pmid: 12535522
references.citation: Autophagy. 2013 Dec;9(12):1965-74
references.pmid: 24185444
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6403-8
references.pmid: 15084750
references.citation: Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):11883-8
references.pmid: 10518545
references.citation: Mol Cell Biol. 1996 Nov;16(11):6020-8
references.pmid: 8887631
references.citation: Genome Res. 2012 Feb;22(2):386-97
references.pmid: 21940837
references.citation: Brain. 2011 Jan;134(Pt 1):258-77
references.pmid: 21186265
references.citation: PLoS Genet. 2011 Jun;7(6):e1002119
references.pmid: 21695230
references.citation: PLoS Genet. 2013;9(12):e1004020
references.pmid: 24385923
references.citation: Mol Cell Biol. 1998 Sep;18(9):5091-8
references.pmid: 9710593
references.citation: J Biol Chem. 1999 Oct 15;274(42):29655-65
references.pmid: 10514435
references.citation: Free Radic Biol Med. 2014 Jun;71:303-320
references.pmid: 24681338
references.citation: Dev Biol. 1998 Jun 15;198(2):286-302
references.pmid: 9659934
references.citation: J Cell Sci. 2003 May 1;116(Pt 9):1679-88
references.pmid: 12665549
references.citation: Biochem Soc Trans. 2007 Feb;35(Pt 1):12-7
references.pmid: 17212580
references.citation: Cytometry A. 2007 Feb;71(2):114-23
references.pmid: 17200959
references.citation: Mol Cell. 2010 Apr 9;38(1):17-28
references.pmid: 20385086
references.citation: Mol Cell Biol. 1998 Jan;18(1):30-8
references.pmid: 9418850
references.citation: Am J Pathol. 2012 Mar;180(3):963-972
references.pmid: 22210478
references.citation: Biochem Biophys Res Commun. 2014 May 2;447(2):292-8
references.pmid: 24727455
references.citation: Cell Metab. 2013 Jan 8;17(1):85-100
references.pmid: 23312285
references.citation: Nat Commun. 2013;4:2267
references.pmid: 23925298
references.citation: FEBS Lett. 2003 Jul 10;546(2-3):228-32
references.pmid: 12832045
references.citation: Mol Cell Biol. 2009 Feb;29(4):1095-106
references.pmid: 19075009
references.citation: EMBO J. 2001 Aug 1;20(15):4003-12
references.pmid: 11483504
references.citation: Annu Rev Biochem. 2009;78:477-513
references.pmid: 19489727
references.citation: Annu Rev Biochem. 1998;67:425-79
references.pmid: 9759494
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 8;103(32):12173-8
references.pmid: 16880390
references.citation: J Microsc. 2013 Dec;252(3):295-302
references.pmid: 24117417
references.citation: Mol Cell. 2001 Dec;8(6):1339-49
references.pmid: 11779508
references.citation: PLoS One. 2006 Dec 20;1:e77
references.pmid: 17183709
references.citation: Aging Cell. 2013 Oct;12(5):802-13
references.pmid: 23738891