PMID- 29581234
OWN - NLM
STAT- MEDLINE
DCOM- 20190122
LR  - 20210317
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 293
IP  - 19
DP  - 2018 May 11
TI  - TRAF-interacting protein with forkhead-associated domain (TIFA) transduces DNA 
      damage-induced activation of NF-kappaB.
PG  - 7268-7280
LID - S0021-9258(20)39215-2 [pii]
LID - 10.1074/jbc.RA117.001684 [doi]
AB  - DNA damage-induced NF-kappaB activation and the secretion of inflammatory cytokines 
      play crucial roles in carcinogenesis and cellular senescence. However, the 
      underlying mechanisms, especially the initial sensors and transducers connecting 
      the nuclear DNA damage signal with cytoplasmic NF-kappaB activation remain 
      incompletely understood. Here, we report that TRAF-interacting protein with 
      forkhead-associated domain (TIFA), an established NF-kappaB activator in the cytosol, 
      unexpectedly exhibited nuclear translocation and accumulation on damaged 
      chromatin following genotoxic stress. Accordingly, we also found that DNA 
      damage-induced transcriptional activation and the resulting secretion of classic 
      NF-kappaB targets, including interleukin (IL)-6 and IL-8, was greatly enhanced in 
      TIFA-overexpressing cells compared with control cells. Mechanistically, DNA 
      damage-induced TIFA phosphorylation at threonine 9 (pThr-9), and this 
      phosphorylation event, involving the pThr-binding forkhead-associated domain, was 
      crucial for its enrichment on damaged chromatin and subsequent NF-kappaB activation. 
      Moreover, in conjunction with its partner protein, the E3 ligase TNF 
      receptor-associated factor 2 (TRAF2), TIFA relayed the DNA damage signals by 
      stimulating ubiquitination of NF-kappaB essential modulator (NEMO), whose 
      sumoylation, phosphorylation, and ubiquitination were critical for NF-kappaB's 
      response to DNA damage. Consistently, TRAF2 knockdown suppressed TIFA 
      overexpression-enhanced NEMO ubiquitination under genotoxic stress, and a 
      unphosphorylatable Thr-9-mutated TIFA variant had only minor effects on NEMO 
      poly-ubiquitination. Finally, in agreement with the model of DNA 
      damage-associated secretory senescence barrier against carcinogenesis, ectopic 
      TIFA expression limited proliferation of multiple myeloma cancer cells. In 
      conclusion our results indicate that TIFA functions as a key transducer in DNA 
      damage-induced NF-kappaB activation.
CI  - (c) 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Fu, Jingxuan
AU  - Fu J
AD  - Peking University Research Center on Aging, Beijing 100191; Department of 
      Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking 
      University Health Science Center, Beijing 100191.
FAU - Huang, Daoyuan
AU  - Huang D
AD  - Peking University Research Center on Aging, Beijing 100191; Department of 
      Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking 
      University Health Science Center, Beijing 100191.
FAU - Yuan, Fuwen
AU  - Yuan F
AD  - Peking University Research Center on Aging, Beijing 100191; Department of 
      Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking 
      University Health Science Center, Beijing 100191.
FAU - Xie, Nan
AU  - Xie N
AD  - Peking University Research Center on Aging, Beijing 100191; Department of 
      Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking 
      University Health Science Center, Beijing 100191.
FAU - Li, Qian
AU  - Li Q
AD  - Department of Orthodontics, Peking University School and Hospital of Stomatology, 
      National Engineering Laboratory for Digital and Material Technology of 
      Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing 100081, 
      People's Republic of China.
FAU - Sun, Xinpei
AU  - Sun X
AD  - Peking University Research Center on Aging, Beijing 100191; Department of 
      Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking 
      University Health Science Center, Beijing 100191.
FAU - Zhou, Xuehong
AU  - Zhou X
AD  - Department of Biochemistry and Molecular Biology, School of Basic Medical 
      Sciences, Peking University Health Science Center, Beijing 100191.
FAU - Li, Guodong
AU  - Li G
AD  - Peking University Research Center on Aging, Beijing 100191; Department of 
      Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking 
      University Health Science Center, Beijing 100191.
FAU - Tong, Tanjun
AU  - Tong T
AD  - Peking University Research Center on Aging, Beijing 100191; Department of 
      Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking 
      University Health Science Center, Beijing 100191. Electronic address: 
      ttj@bjmu.edu.cn.
FAU - Zhang, Yu
AU  - Zhang Y
AD  - Peking University Research Center on Aging, Beijing 100191; Department of 
      Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking 
      University Health Science Center, Beijing 100191. Electronic address: 
      zhang_yu@hsc.pku.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180326
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (CXCL8 protein, human)
RN  - 0 (Chromatin)
RN  - 0 (IKBKG protein, human)
RN  - 0 (IL6 protein, human)
RN  - 0 (Interleukin-6)
RN  - 0 (Interleukin-8)
RN  - 0 (Mutagens)
RN  - 0 (NF-kappa B)
RN  - 0 (PSMD2 protein, human)
RN  - 0 (TIFA protein, human)
RN  - 0 (TNF Receptor-Associated Factor 2)
RN  - 0 (Tumor Necrosis Factor Receptor-Associated Peptides and Proteins)
RN  - EC 2.7.11.10 (I-kappa B Kinase)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/*metabolism
MH  - Carcinogenesis
MH  - Cell Proliferation
MH  - Chromatin/metabolism
MH  - *DNA Damage
MH  - HEK293 Cells
MH  - HeLa Cells
MH  - Humans
MH  - I-kappa B Kinase/metabolism
MH  - Interleukin-6/metabolism
MH  - Interleukin-8/metabolism
MH  - Multiple Myeloma/metabolism/pathology
MH  - Mutagens/toxicity
MH  - NF-kappa B/*metabolism
MH  - Phosphorylation
MH  - Protein Binding
MH  - Signal Transduction
MH  - TNF Receptor-Associated Factor 2/metabolism
MH  - Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/*metabolism
MH  - Ubiquitination
PMC - PMC5950011
OTO - NOTNLM
OT  - DNA damage
OT  - NEMO
OT  - NF-kappaB transcription factor
OT  - TIFA
OT  - TNF receptor associated factor (TRAF)
OT  - TRAF-interacting protein with forkhead-associated domain
OT  - carcinogenesis
OT  - ubiquitylation (ubiquitination)
COIS- The authors declare that they have no conflicts of interest with the contents of 
      this article
EDAT- 2018/03/28 06:00
MHDA- 2019/01/23 06:00
PMCR- 2019/05/11
CRDT- 2018/03/28 06:00
PHST- 2017/12/29 00:00 [received]
PHST- 2018/03/23 00:00 [revised]
PHST- 2018/03/28 06:00 [pubmed]
PHST- 2019/01/23 06:00 [medline]
PHST- 2018/03/28 06:00 [entrez]
PHST- 2019/05/11 00:00 [pmc-release]
AID - S0021-9258(20)39215-2 [pii]
AID - RA117.001684 [pii]
AID - 10.1074/jbc.RA117.001684 [doi]
PST - ppublish
SO  - J Biol Chem. 2018 May 11;293(19):7268-7280. doi: 10.1074/jbc.RA117.001684. Epub 
      2018 Mar 26.