An LRP16-containing preassembly complex contributes to NF-κB activation induced by DNA double-strand breaks.
The activation of NF-κB has emerged as an important mechanism for the modulation of the response to DNA double-strand breaks (DSBs). The concomitant SUMOylation and phosphorylation of IKKγ by PIASy and ATM, respectively, is a key event in this mechanism. However, the mechanism through which mammalian cells are able to accomplish these IKKγ modifications in a timely and lesion-specific manner remains unclear. In this study, we demonstrate that LRP16 constitutively interacts with PARP1 and IKKγ. This interaction is essential for efficient interactions among PARP1, IKKγ, and PIASy, the modifications of IKKγ, and the activation of NF-κB following DSB induction. The regulation of LRP16 in NF-κB activation is dependent on the DSB-specific sensors Ku70/Ku80. These data strongly suggest that LRP16, through its constitutive interactions with PARP1 and IKKγ, functions to facilitate the lesion-specific recruitment of PARP1 and IKKγ and, ultimately, the concomitant recruitment of PIASy to IKKγ in response to DSB damage. Therefore, the study has provided important new mechanistic insights concerning DSB-induced NF-κB activation.
Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, Beijing, 100853, China.
Zhiqiang
Z
Wu
Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, Beijing, 100853, China.
Chunmeng
C
Wang
Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, Beijing, 100853, China.
Miaomiao
M
Bai
Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, Beijing, 100853, China.
Xiaolei
X
Li
Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, Beijing, 100853, China.
Qian
Q
Mei
Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, Beijing, 100853, China.
Xiang
X
Li
Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, Beijing, 100853, China.
Yao
Y
Wang
Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, Beijing, 100853, China.
Xiaobing
X
Fu
Department of Genetics & Genome Sciences, Case Comprehensive Cancer Center, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH 44106, USA.
Guangbin
G
Luo
Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, Beijing, 100853, China hanwdrsw69@yahoo.com.
Weidong
W
Han
D034961:Antigens, Nuclear / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000378:metabolism; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D000072200:Ku Autoantigen; D061986:MCF-7 Cells; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058207:Sumoylation
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; D016328:NF-kappa B; D009363:Neoplasm Proteins; C485891:PIAS4 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D051550:I-kappa B Kinase; D002265:Carboxylic Ester Hydrolases; C476832:MACROD1 protein, human; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen