KAT2A and KAT2B prevent double-stranded RNA accumulation and interferon signaling to maintain intestinal stem cell renewal.

Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101653440 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2375-2548 (Electronic) Linking ISSN: 23752548 NLM ISO Abbreviation: Sci Adv Subsets: MEDLINE

Original Publication: Washington, DC : American Association for the Advancement of Science, [2015]-

Signal Transduction* ; RNA, Double-Stranded*/metabolism ; Stem Cells*/metabolism ; Stem Cells*/cytology ; Interferons*/metabolism ; Mice, Knockout* ; Histone Acetyltransferases*/metabolism ; Histone Acetyltransferases*/genetics; Animals ; Mice ; Intestinal Mucosa/metabolism ; Intestinal Mucosa/cytology ; Mitochondria/metabolism ; Cell Self Renewal/genetics ; Intestines/cytology

Histone acetyltransferases KAT2A and KAT2B are paralogs highly expressed in the intestinal epithelium, but their functions are not well understood. In this study, double knockout of murine Kat2 genes in the intestinal epithelium was lethal, resulting in robust activation of interferon signaling and interferon-associated phenotypes including the loss of intestinal stem cells. Use of pharmacological agents and sterile organoid cultures indicated a cell-intrinsic double-stranded RNA trigger for interferon signaling. Acetyl-proteomics and sequencing of immunoprecipitated double-stranded RNA were used to interrogate the mechanism behind this response, which identified mitochondria-encoded double-stranded RNA as the source of intrinsic interferon signaling. Kat2a and Kat2b therefore play an essential role in regulating mitochondrial functions and maintaining intestinal health.

Update of: bioRxiv. 2023 Sep 05:2023.09.04.556156. doi: 10.1101/2023.09.04.556156. (PMID: 37732252)

J Crohns Colitis. 2016 Jun;10(6):726-34. (PMID: 26802082)
J Biol Chem. 2000 Jun 2;275(22):17211-20. (PMID: 10747963)
Proc Natl Acad Sci U S A. 2017 Feb 21;114(8):E1432-E1440. (PMID: 28167773)
Gut. 2005 Dec;54(12):1802-9. (PMID: 16284290)
Cell. 2014 Oct 9;159(2):458-458.e1. (PMID: 25303536)
Bioinformatics. 2015 Jan 15;31(2):166-9. (PMID: 25260700)
Mol Cell Proteomics. 2014 Nov;13(11):2896-910. (PMID: 25106422)
Immunity. 2005 Aug;23(2):165-75. (PMID: 16111635)
Biomolecules. 2021 Jan 22;11(2):. (PMID: 33499062)
Nucleic Acids Res. 2011 Mar;39(4):1390-7. (PMID: 20972224)
Nat Rev Mol Cell Biol. 2022 Apr;23(4):286-301. (PMID: 34815573)
Cold Spring Harb Perspect Biol. 2014 Jul 01;6(7):a018762. (PMID: 24984779)
Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11303-6. (PMID: 11027331)
Cell Rep. 2017 Aug 29;20(9):1997-2009. (PMID: 28854354)
Cell Death Dis. 2022 Mar 14;13(3):237. (PMID: 35288533)
Nature. 1996 Sep 19;383(6597):269-72. (PMID: 8805705)
Neurochem Res. 2003 Dec;28(12):1805-12. (PMID: 14649721)
EMBO J. 2009 Jul 8;28(13):1878-89. (PMID: 19407812)
Nature. 2009 May 14;459(7244):262-5. (PMID: 19329995)
Sci Rep. 2020 Sep 8;10(1):14639. (PMID: 32901054)
Genome Biol. 2009;10(3):R25. (PMID: 19261174)
Mol Cell Biol. 2014 Oct 1;34(19):3746-53. (PMID: 25071153)
J Proteome Res. 2018 Jul 6;17(7):2533-2541. (PMID: 29790754)
Front Immunol. 2020 Dec 11;11:608645. (PMID: 33362795)
Nucleic Acids Res. 2016 Jul 8;44(W1):W160-5. (PMID: 27079975)
Nat Rev Immunol. 2016 Sep;16(9):566-80. (PMID: 27455396)
Nucleic Acids Res. 2021 Jan 8;49(D1):D916-D923. (PMID: 33270111)
Genome Biol. 2014;15(12):550. (PMID: 25516281)
J Biol Chem. 1999 Feb 26;274(9):5895-900. (PMID: 10026213)
J Exp Med. 2018 May 7;215(5):1287-1299. (PMID: 29622565)
Chembiochem. 2008 Mar 3;9(4):499-503. (PMID: 18247445)
EMBO J. 2011 Jan 19;30(2):249-62. (PMID: 21131905)
Nat Cell Biol. 2020 Aug;22(8):919-926. (PMID: 32690888)
Dev Growth Differ. 2008 Jun;50(5):321-30. (PMID: 18430026)
Genesis. 2004 Jul;39(3):186-93. (PMID: 15282745)
PLoS Genet. 2018 May 16;14(5):e1007386. (PMID: 29768408)
Physiology (Bethesda). 2020 Sep 1;35(5):302-327. (PMID: 32783608)
J Biol Chem. 1999 Jan 15;274(3):1189-92. (PMID: 9880483)
Nat Genet. 2000 May;25(1):25-9. (PMID: 10802651)
Dev Dyn. 2007 Jun;236(6):1547-57. (PMID: 17440986)
Cell Death Dis. 2022 Apr 30;13(4):421. (PMID: 35490166)
Elife. 2022 Oct 21;11:. (PMID: 36269050)
Biochem Cell Biol. 2019 Feb;97(1):30-45. (PMID: 29671337)
PLoS One. 2011;6(12):e28417. (PMID: 22162770)
J Mol Cell Cardiol. 2018 Jan;114:185-198. (PMID: 29174768)
Oncogene. 2007 Aug 13;26(37):5341-57. (PMID: 17694077)
Nat Commun. 2016 Oct 31;7:13227. (PMID: 27796307)
Cell Stem Cell. 2011 May 6;8(5):511-24. (PMID: 21419747)
Cell Rep. 2022 Aug 9;40(6):111178. (PMID: 35947956)
Noncoding RNA. 2021 Feb 19;7(1):. (PMID: 33669629)
Blood Cancer Discov. 2023 Jan 6;4(1):12-33. (PMID: 36322781)
Signal Transduct Target Ther. 2021 Apr 30;6(1):170. (PMID: 33927185)
Bioinformatics. 2010 Jan 1;26(1):139-40. (PMID: 19910308)
Mol Cell Oncol. 2016 Dec 16;4(2):e1270391. (PMID: 28401181)
J Virol. 2020 Oct 14;94(21):. (PMID: 32847859)
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50. (PMID: 16199517)
Chem Rev. 2015 Mar 25;115(6):2274-95. (PMID: 25424540)
Biochim Biophys Acta. 2016 Oct;1863(10):2362-78. (PMID: 26968366)
Nat Methods. 2017 Apr;14(4):381-387. (PMID: 28263961)
Biol Chem. 2016 Dec 20;398(3):303-317. (PMID: 27727142)
Dev Dyn. 2008 Apr;237(4):928-40. (PMID: 18330926)
Bioinformatics. 2013 Jan 1;29(1):15-21. (PMID: 23104886)
PLoS Pathog. 2008 Mar 14;4(3):e1000017. (PMID: 18369468)
Nature. 2023 May;617(7962):818-826. (PMID: 37198486)
Mol Cell Biol. 1998 Oct;18(10):5659-69. (PMID: 9742083)
Nature. 2017 Dec 14;552(7684):273-277. (PMID: 29211711)
Oncol Rep. 2014 Nov;32(5):2260-6. (PMID: 25174320)
Cell. 2011 Aug 19;146(4):645-58. (PMID: 21854988)
Nature. 2000 Jan 6;403(6765):41-5. (PMID: 10638745)
Cancers (Basel). 2019 May 24;11(5):. (PMID: 31137727)
Front Immunol. 2020 Apr 03;11:587. (PMID: 32308658)
STAR Protoc. 2021 Mar 18;2(1):100366. (PMID: 33778776)
Genome Res. 2017 Mar;27(3):491-499. (PMID: 28100584)
Nature. 2018 Aug;560(7717):238-242. (PMID: 30046113)
Nat Genet. 2000 Oct;26(2):229-32. (PMID: 11017084)
Nature. 2020 Apr;580(7803):386-390. (PMID: 32296174)
Gut. 2021 Mar;70(3):485-498. (PMID: 32503845)
EMBO Rep. 2014 Nov;15(11):1192-201. (PMID: 25269644)
Bioinformatics. 2009 Aug 15;25(16):2078-9. (PMID: 19505943)
Nature. 2017 Nov 16;551(7680):333-339. (PMID: 29144463)
Front Immunol. 2022 Jan 03;12:779667. (PMID: 35046941)
J Vis Exp. 2016 May 17;(111):. (PMID: 27286567)
Methods Mol Biol. 2013;945:319-28. (PMID: 23097115)
Methods Mol Biol. 2023;2589:345-360. (PMID: 36255636)
Structure. 2017 Apr 4;25(4):650-654.e2. (PMID: 28286003)
J Biol Chem. 2003 Oct 10;278(41):39402-12. (PMID: 12885766)
J Biol Chem. 2015 Nov 27;290(48):28997-9009. (PMID: 26468280)
Biochemistry. 2014 Jun 17;53(23):3817-29. (PMID: 24884163)
ACS Med Chem Lett. 2019 Mar 11;10(5):780-785. (PMID: 31097999)
J Biol Chem. 2017 May 5;292(18):7295-7303. (PMID: 28289095)
J Cell Sci. 2023 Jun 15;136(12):. (PMID: 37259855)

P30 CA072720 United States CA NCI NIH HHS; R01 DK126446 United States DK NIDDK NIH HHS; R35 GM131678 United States GM NIGMS NIH HHS; S10 OD025140 United States OD NIH HHS; F31 CA254086 United States CA NCI NIH HHS; R01 DK121915 United States DK NIDDK NIH HHS

0 (RNA, Double-Stranded)
9008-11-1 (Interferons)
EC 2.3.1.48 (Histone Acetyltransferases)

Date Created: 20240807 Date Completed: 20240807 Latest Revision: 20240813

20240813

PMC11305398

10.1126/sciadv.adl1584

39110797