Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-kappaB and beta-amyloid precursor protein.
Defining the molecular mechanisms that integrate diverse signaling pathways at the level of gene transcription remains a central issue in biology. Here, we demonstrate that interleukin-1beta (IL-1beta) causes nuclear export of a specific N-CoR corepressor complex, resulting in derepression of a specific subset of NF-kappaB-regulated genes, exemplified by the tetraspanin KAI1 that regulates membrane receptor function. Nuclear export of the N-CoR/TAB2/HDAC3 complex by IL-1beta is temporally linked to selective recruitment of a Tip60 coactivator complex. Surprisingly, KAI1 is also directly activated by a ternary complex, dependent on the acetyltransferase activity of Tip60, consisting of the presenilin-dependent C-terminal cleavage product of the amyloid beta precursor protein (APP), Fe65, and Tip60, identifying a specific in vivo gene target of an APP-dependent transcription complex in the brain.
Baek
Sung Hee
SH
Howard Hughes Medical Institute, Department of Molecular Medicine, La Jolla, CA 92093, USA.
Ohgi
Kenneth A
KA
Rose
David W
DW
Koo
Edward H
EH
Glass
Christopher K
CK
Rosenfeld
Michael G
MG
D000123:Acetyltransferases / Q000235:genetics / Q000502:physiology; D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D015703:Antigens, CD; D002352:Carrier Proteins / Q000502:physiology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D051548:Histone Acetyltransferases; D006801:Humans; D007375:Interleukin-1 / Q000502:physiology*; D051861:Kangai-1 Protein; D000074443:Lysine Acetyltransferase 5; D048728:MAP Kinase Kinase Kinase 1; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000502:physiology; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D056971:Nuclear Receptor Co-Repressor 1; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000096:biosynthesis; D012097:Repressor Proteins / Q000502:physiology*; D015398:Signal Transduction; D015854:Up-Regulation
C091042:APBB1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; D015703:Antigens, CD; C497688:CD82 protein, human; D002352:Carrier Proteins; D007375:Interleukin-1; D051861:Kangai-1 Protein; D008562:Membrane Glycoproteins; C539127:NCOR1 protein, human; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C410585:TAB2 protein, human; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; D017346:Protein Serine-Threonine Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human