title: Identification of a tissue-selective heat shock response regulatory network.
abstract: The heat shock response (HSR) is essential to survive acute proteotoxic stress and has been studied extensively in unicellular organisms and tissue culture cells, but to a lesser extent in intact metazoan animals. To identify the regulatory pathways that control the HSR in Caenorhabditis elegans, we performed a genome-wide RNAi screen and identified 59 genes corresponding to 7 positive activators required for the HSR and 52 negative regulators whose knockdown leads to constitutive activation of the HSR. These modifiers function in specific steps of gene expression, protein synthesis, protein folding, trafficking, and protein clearance, and comprise the metazoan heat shock regulatory network (HSN). Whereas the positive regulators function in all tissues of C. elegans, nearly all of the negative regulators exhibited tissue-selective effects. Knockdown of the subunits of the proteasome strongly induces HS reporter expression only in the intestine and spermatheca but not in muscle cells, while knockdown of subunits of the TRiC/CCT chaperonin induces HS reporter expression only in muscle cells. Yet, both the proteasome and TRiC/CCT chaperonin are ubiquitously expressed and are required for clearance and folding in all tissues. We propose that the HSN identifies a key subset of the proteostasis machinery that regulates the HSR according to the unique functional requirements of each tissue.
authors: Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois, United States of America.
authors: Eric
authors: E
authors: Guisbert
authors: Daniel M
authors: DM
authors: Czyz
authors: Klaus
authors: K
authors: Richter
authors: Patrick D
authors: PD
authors: McMullen
authors: Richard I
authors: RI
authors: Morimoto
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics; D018869:Heat-Shock Response / Q000235:genetics; D017510:Protein Folding; D011506:Proteins / Q000235:genetics; D034622:RNA Interference
chemical_list: D006360:Heat-Shock Proteins; D011506:Proteins
references: Genes Dev. 1998 Mar 1;12(5):654-66
references: 9499401
references: PLoS Genet. 2007 Apr 6;3(4):e56
references: 17411345
references: J Stat Mech. 2005 Feb 1;2005(P02001):nihpa35573
references: 18159217
references: Science. 2008 May 9;320(5877):811-4
references: 18467592
references: J Struct Biol. 2001 Aug;135(2):176-84
references: 11580267
references: Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8695-9
references: 8078944
references: Mol Cell Biol. 1998 Sep;18(9):5091-8
references: 9710593
references: Nature. 2002 Jan 3;415(6867):92-6
references: 11780124
references: EMBO J. 1999 Nov 1;18(21):5943-52
references: 10545106
references: Science. 2009 Jan 30;323(5914):630-3
references: 19179530
references: Nature. 2003 Jul 17;424(6946):277-83
references: 12845331
references: PLoS Genet. 2011 Jul;7(7):e1002206
references: 21829383
references: EMBO J. 1997 May 1;16(9):2452-62
references: 9171358
references: Cell Stress Chaperones. 1999 Dec;4(4):235-42
references: 10590837
references: J Neurosci. 2003 Jul 2;23(13):5789-98
references: 12843283
references: PLoS Genet. 2012;8(7):e1002792
references: 22829775
references: Science. 2006 Mar 10;311(5766):1481-4
references: 16527984
references: PLoS Genet. 2011 Dec;7(12):e1002438
references: 22242008
references: Genetics. 2004 Dec;168(4):1937-49
references: 15611166
references: Cell. 1987 Dec 4;51(5):763-72
references: 3119225
references: PLoS Genet. 2005 Jul;1(1):119-28
references: 16103914
references: Nat Methods. 2011 Feb;8(2):135-8
references: 21240281
references: Mol Cell Biol. 2008 Jul;28(13):4261-74
references: 18458060
references: Nucleic Acids Res. 2010 Jan;38(Database issue):D463-7
references: 19910365
references: Trends Biochem Sci. 1991 Apr;16(4):135-40
references: 1877088
references: Mol Cell Biol. 1987 Mar;7(3):1129-38
references: 3561411
references: Genes Dev. 2002 Dec 15;16(24):3186-98
references: 12502740
references: Phys Rev E Stat Nonlin Soft Matter Phys. 2004 Feb;69(2 Pt 2):026113
references: 14995526
references: Science. 1990 Nov 23;250(4984):1111-7
references: 1701272
references: Nat Rev Mol Cell Biol. 2010 Aug;11(8):545-55
references: 20628411
references: Mol Biol Cell. 2004 Feb;15(2):657-64
references: 14668486
references: J Biol Chem. 1996 Oct 4;271(40):24769-75
references: 8798747
references: Oncogene. 2008 Mar 20;27(13):1886-93
references: 17922035
references: Mol Biol Cell. 1999 Jul;10(7):2101-17
references: 10397752
references: Cell. 2012 Apr 13;149(2):452-66
references: 22500807
references: Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):14914-9
references: 19706382
references: Cell. 1998 Aug 21;94(4):471-80
references: 9727490
references: Proc Natl Acad Sci U S A. 1987 Apr;84(8):2203-7
references: 3031671
references: PLoS Genet. 2008 Feb 29;4(2):e1000021
references: 18454197
references: Nature. 2003 Jan 16;421(6920):231-7
references: 12529635
references: Genetics. 2011 Apr;187(4):1235-40
references: 21288877
references: FEBS Lett. 2005 Jun 6;579(14):3063-8
references: 15907843
references: J Cell Sci. 2004 Aug 15;117(Pt 18):4055-66
references: 15280428
references: WormBook. 2005 Dec 01;:1-24
references: 18050424
references: Genetics. 1974 May;77(1):71-94
references: 4366476
references: Mol Cell Biol. 1993 Sep;13(9):5427-38
references: 8355691
references: J Biol Chem. 1994 Dec 2;269(48):30412-8
references: 7982955
references: J Cell Biol. 1992 Jun;117(6):1151-9
references: 1607379
references: PLoS Biol. 2010 Jan 19;8(1):e1000291
references: 20098725
references: J Biol Chem. 1990 Sep 5;265(25):15275-9
references: 1697588
references: Genes Dev. 1992 Jul;6(7):1153-64
references: 1628823
references: Mol Cell Biol. 1987 Oct;7(10):3646-55
references: 2824993
references: Mol Cell Biol. 1989 Jun;9(6):2574-87
references: 2474756
references: Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6403-8
references: 15084750
references: Genes Dev. 2008 Jun 1;22(11):1427-38
references: 18519635
references: J Neurosci. 1996 Jan 15;16(2):478-85
references: 8551332
references: Science. 2003 May 16;300(5622):1142-5
references: 12750521
references: Nat Rev Mol Cell Biol. 2007 Jul;8(7):519-29
references: 17565364
references: Cold Spring Harb Symp Quant Biol. 2003;68:159-69
references: 15338614
references: PLoS Genet. 2010 Aug 05;6(8):
references: 20700440
references: Cell. 1984 Jul;37(3):979-91
references: 6430570
references: Genes Dev. 2004 Nov 15;18(22):2812-21
references: 15545634
references: Immunol Today. 1999 Dec;20(12):582-8
references: 10562710
references: Mol Cell Biol. 1991 Jan;11(1):586-92
references: 1986252